ST-246 (tecovirimat monohydrate) suspension formulations

ABSTRACT

The present invention is directed to a dry suspension for reconstitution containing Tecovirimat (ST-246) powder and simethicone. The dry suspension is dispersed in water to provide an aqueous pharmaceutical suspension formulation for oral administration for treating orthopoxvirus infections and/or eczema vaccinatum. The suspension formulation exhibits excellent stability and good dissolution and has an improved taste and texture.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation application of U.S.application Ser. No. 16/071,119 filed Jul. 19, 2018 which is a § 371National Phase application based on PCT/US2017/017915 filed Feb. 15,2017 which claims the benefit of U.S. provisional application No.62/295,710 filed Feb. 16, 2016 the subject matter of each of which isincorporated by reference in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with U.S. government support under Contract No.:IIIISO100201100001C awarded by the Biomedical Advanced Research andDevelopment Authority (BARDA). The U.S. government has certain rights inthis invention.

FIELD OF THE INVENTION

The present invention relates to a novel oral powder for suspension (drysuspension) containing Tecovirimat (ST-246) powder for reconstitutionand a process for making the dry suspension. The dry suspensions aredispersed in water to provide aqueous pharmaceutical suspensionformulations for oral administration.

BACKGROUND OF THE INVENTION

Throughout this application, various publications are referenced withinthe text. The disclosure of these publications in their entireties arehereby incorporated by reference into this application in order to morefully describe the state of the art as known to those skilled in thereinas of the date of the invention described and claimed herein.

Historically, variola virus, the etiologic agent of smallpox, has beenestimated to have killed, crippled, or disfigured nearly 10% of thehuman population prior to eradication (1). Smallpox is highlycommunicable and carries exceptionally high morbidity. Secondary attackrates among unvaccinated members of households in which someone hadsmallpox have been reported to range from r30% to 80%. Mortality ratesrange from 1% for variola minor to 30% for variola major. With theadvent of biowarfare as an instrument of terrorism, smallpox can nolonger be thought of as a disease of historic impact only.

There are currently no therapies other than early vaccination that canalter the outcome of disease or potentially prevent disease in apopulation that has been exposed to smallpox. Vaccination carries aninherent risk of adverse events for certain immunosuppressed recipientsand even some healthy recipients (2). Moreover, vaccination is effectiveonly if administered within 4 days post-exposure. Thus, antiviral drugsused alone or potentially in combination with vaccination can be used totreat individuals during the window of vulnerability which occurs priorto development of protective immunity. Additionally, antiviral drugscould also be used in the treatment of zoonotic poxvirus disease inhumans, such as monkeypox.

ST-246(4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(III)-yl)-benzamide)(Tecrovirmat),has recently emerged as a potent candidate against orthopoxvirus.Several studies evaluating ST-246 for activity against orthopoxviruseshave demonstrated excellent in vitro and in vivo efficacy (3, 4). Whenevaluated in vitro against vaccinia virus (VV), cowpox virus (CV),ectromelia virus (ECTV), monkeypox, camelpox, and variola viruses,ST-246 inhibited virus replication by 50% (50% effective concentration[EC50]) at or below a concentration of 0.07 μM. With animal models usinglethal infections with ECTV, VV, or CV, ST-246 was reported to benontoxic and highly effective in preventing or reducing mortality evenwhen treatments were delayed up to 72 h post-viral inoculation (3, 4).ST-246 was also evaluated with the nonlethal mouse tail lesion modelusing intravenous VV. When ST-246 was administered orally twice a day at15 or 50 mg/kg of body weight for 5 days, the tail lesions weresignificantly reduced (4). Most recently, an infant was given ST-246 asan FDA-authorized emergency treatment for eczema vaccinatum whichdeveloped after exposure to the parent's predeployment military smallpoximmunization (5).

Given the high efficacy of ST-246 antiviral therapy against smallpox anda lack of FDA-approved medications for the treatment of smallpoxinfection, there is clearly a need for developing safe and effectiveST-246 formulations that can be administered by various routes ofadministration. However, the poor solubility of ST-246 in water and inpharmaceutically acceptable pH buffers and commonly used pharmaceuticalvehicles such as co-solvents, surfactants, complexing agents, and lipidscreates an impediment to making safe and effective ST-246 liquidformulations.

Thus, there is a critical need in the pharmaceutical and otherbiological based industries to formulate water insoluble ST-246 intoliquid suspensions for oral, parenteral, or topical administration.

However, the preparation of an aqueous pharmaceutical suspensionformulation from micronized ST-246 presents problems that are difficultto overcome, such as retaining the colloidal stability, preventingparticle size growth and foaming.

Furthermore, once an aqueous suspension has been prepared, sedimentationof the suspension should be avoided. However, if sedimentation arises,the restoration of the suspension must be achieved as easily and asquickly as possible and advantageously this should be achieved by simplyshaking the mixture by hand.

Failure to attain rapid reconstitution of the suspension results in anunacceptably high risk of a dosage error. Furthermore, rapidreconstitution is crucial given that the suspension is often dispensedusing a dropper or a dispensing syringe, thereby requiring a stableliquid suspension which is able to flow freely from the dispensingdevices and ensure that significantly less material sticks therein.

Additionally, foaming of the suspension formulation should be avoided,given that this also results in the dosage being imprecise anduncertain.

Finally, suspension formulations that are used for oral administration,particularly for pediatric use, must not have a bitter taste.

SUMMARY OF THE INVENTION

The present invention provides an oral powder for suspension (drysuspension) containing4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2-(1H)-yl)-benzamide,commonly known as Tecovirimat or ST-246, granulated powder andsimethicone, which is suitable for reconstitution.

The present invention also provides a process for making the drysuspension comprising mixing ST-246 powder with simethicone.

The present invention further provides an aqueous pharmaceuticalsuspension formulation comprising ST-246, simethicone and a suspendingagent for oral administration.

Additionally, the present invention provides a process for making theaqueous pharmaceutical suspension formulation comprising dispersing thedry suspension and a suspending agent in water.

The present invention also provides methods of treating orthopoxvirusinfections and/or eczema vaccinatum comprising administering to asubject in need thereof an aqueous pharmaceutical suspension formulationaccording to the present invention.

These and other objects, advantages, and features of the invention willbecome apparent to those persons skilled in the art upon reading thedetails of the methods and formulations as more fully described below.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the % ST-246 release from formulations DS 54, 55, 57 and58.

FIG. 2 shows the % ST-246 release from formulations DS 75, 77, 83 and84.

FIG. 3 shows the dissolution of ST-246 from formulations DS 85, 86, and87.

FIG. 4 shows the % ST-246 release from formulation DS 88 at differentblending times.

FIG. 5 shows the % ST-246 release from DS 88 at different lubricationtimes.

FIG. 6 shows the % ST-246 release from DS 89 and 90.

FIG. 7 shows the % ST-246 release from DS 91 and 92.

FIG. 8A shows an observation that when passing undiluted simethiconethrough #20 screen the simethicone granules stick on the screen. FIG. 8Bshows an observation when passing undiluted simethicone granules through#20 screen the simethicone granules stick on the screen. FIG. 8C shownan observation that when passing pre-diluted simethicone through #20screen the simethicone granules passed through the screen easily withoutsticking. FIG. 8D shows an observation that when passing co-milledsimethicone-Tecovirimat granules through #20 screen the co-milledsimethicone-Tecovirimat granules passed easily through the screenwithout sticking.

FIG. 9 shows retained clumps on #20 screen after sieve shaking of 100 gDS-92.

FIG. 10 shows % ST-246 release from DS 93 and 94.

FIG. 11 shows flavor profile definitions, including amplitude, amplitudescale, character notes, intensity scale and aftertaste.

FIG. 12 shows a time intensity profile of musty aromatic off-notes,bitterness and tannin mouthfeel of the Tecovirimat granules lingered atpatient-perceptible levels (≥1) for about 3 minutes in the aftertaste.

FIG. 13 shows a time intensity profile of Tecovirimat formulation #4(micronized API).

FIG. 14 shows a time intensity profile of formulation #1 (strawberry)

FIG. 15 shows a time intensity profile of formulation #2 (cherry)

DETAILED DESCRIPTION OF THE INVENTION

Tecovirimat (ST-246) is an antiviral agent used for smallpox and relatedorthopoxviruses. A suitable oral formulation, according to the presentinvention, is particularly useful in pediatric and/or geriatricpopulations. The typical maximum dosage is 1200 mg/day. The drug hasvery low water solubility over the physiologically relevant pH range,namely approximately 2 μg/mL over a pH range of 1.2 to 6.5. Itssolubility increases slightly above pH 6.5, however the chemicalstability declines. The solution stability is optimum in the pH 4 to 7range, for example the pH 3 to 5 range.

Due to low solubility, preferably the ST-246 is micronized in order toimprove dissolution rate. ST-246 has the potential to undergosupersaturation and crystallization with increased particle size in anaqueous based vehicle, and hence, providing an acceptable ready-to-useliquid/suspension dosage form with better stability and longershelf-life represents a major challenge.

Additionally, when forming a suspension formulation containing ST-246, awetting agent, such as a surfactant, is typically used to improvewetting of ST-246 particles, and also to improve dissolution andsolubility. However, the presence of a surfactant usually leads tofoaming and results in the formulation tasting bitter and having anunpleasant odor.

The present invention provides a powder for a reconstitution product(dry suspension) comprising ST-246 granulated powder and simethiconewhich when suspended in water exhibits acceptable stability anddissolution. Furthermore it has been found that the use of simethiconewith ST-246 provides excellent foam control upon reconstitution.

The present invention provides a similar drug release profile, acritical product attribute for product performance in patients, ascompared to capsule oral dosage form of ST-246.

Additionally, the incorporation of additional excipients, flavoringsand/or sweeteners to the dry suspension and/or the aqueouspharmaceutical suspension formulation improves the taste and texture ofthe formulation.

The dry suspension and/or the suspension formulation may also includeone or more pharmaceutically acceptable ingredients selected from thegroup consisting of disintegrants, carriers, diluents, additives,fillers, lubricants, and binders.

Disintegrants may include agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,pre-gelatinized starch, other starches, clays, other algins, othercelluloses, gums, and mixtures thereof.

Preferably, the dry suspension further comprises at least one suspendingagent.

The suspending agents may include sorbitol syrup; sugar syrup; syntheticpolymers such as carbomer and poloxamer; natural gums such as agar,xanthan gum, and tragacanth; cellulose derivatives (e.g., carboxy methylcellulose, hydroxyl propyl cellulose or methylcellulose); orhydrogenated edible fiats; emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol or fractionated vegetable oils); and preservatives (e.g., methylor propyl-p-hydroxybenzoates or sorbic acid).

The dry suspensions can also contain buffer salts, flavoring, coloringand sweetening agents as appropriate.

Furthermore, the dry suspensions may also contain wetting agents and/orsurface active agents as appropriate.

Preferably, the wetting agent or surface active agent is sodium dodecylsulfate, sodium docusate, tweens, spans, brij, or cetrimide.

Preferably, the suspending agent is methylcellulose and/or hydroxypropylcellulose, and, advantageously, the dry suspension contains bothmethylcellulose and hydroxypropyl cellulose.

Preferably, the dry suspension contains methylcellulose 400 cps and/ormethycellulose 15 cps and, advantageously, the dry suspension containsboth methylcellulose 400 cps and methycellulose 15 cps methylcellulose.

Typically, the dry suspension comprises a lubricant, such as calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof.

Advantageously, the lubricant is magnesium stearate.

Excipients include, but are not limited to, agents used to improvetaste, suspendability, texture, and flavor. In one embodiment, when thedry suspension contains an excipient, the excipient is advantageouslylactose monohydrate. When present, the total amount of excipients aretypically present in an amount of about 10 wt % to about 20 wt %.

The dry suspension may also contain a further antifoaming agent.

Preferably, the dry suspension also contains a sweetener, such assucralose.

Advantageously, the dry suspension contains a flavoring such asstrawberry or black cherry.

The ST-246 may be selected from the group consisting of ST-246 polymorphForm I, ST-246 polymorph Form II, ST-246 polymorph Form III, ST-246polymorph Form IV, ST-246 polymorph Form V and ST-246 polymorph Form VI.

The ST-246 may be micronized and/or granulated with excipients, but isadvantageously micronized and granulated powder.

Furthermore the simethicone may be in granular form or may be in liquidform and adsorbed on lactose monohydrate. Advantageously, thesimethicone is in granular form.

The dry suspension typically contains between 10 to 70 wt % of ST-246,and preferably between 15 to 40 wt % of ST-246.

The dry suspension usually contains between 0.2 to 6.0 wt % simethicone,and preferably between 0.4 to 5.0 wt % simethicone.

Preferably, the dry suspension contains between 1 to 5 wt % ofmethylcellulose, and advantageously, between 2 to 3 wt % ofmethylcellulose.

Preferably, the dry suspension contains between 1.0 to 30 wt % ofhydroxypropylcellulose, and, advantageously, between 2 to 20 wt % ofhydroxypropylcellulose.

When the dry suspension contains a lubricant, typically the lubricant ispresent in the amount 0.1 to 1.0 wt %.

Similarly, when the dry suspension contains a sweetener, typically thesweetener is present in the amount of between 1.0 to 3.0 wt %, and whenthe dry suspension contains a flavoring, typically the flavoring is alsopresent in the amount of between 0.1 to 1.0 wt %.

The dry suspension preferably has an active pharmaceutical ingredient(API) particle size of ST-246 of between 0.5 to 20 μm, or between 0.5 to10 μm, or between 1 μm and 5 μm, and, advantageously, between 1 to 10μm.

It has been found that the higher the API particle size, the slower thedissolution rate.

The present invention also provides an aqueous pharmaceutical suspensionformulation comprising the dry suspension dispersed in water.

Typically the suspension, either dry or liquid, contains a suspendingagent which is preferably selected from the group consisting ofhydromellose, hydroxyethylcellulose, carrageenans, methylcellulose,xanthan gum, povidone, hydroxypropyl cellulose, microcrystallinecellulose, carboxymethylcellulose and sodium alginate.

When the suspension contains water and a suspending agent this istypically referred to as a ‘formulation vehicle’.

Typically, the formulation, upon reconstitution with water, has a pIIbetween 3 and 8, preferably between 5 and 7.

The present invention also provides a method of treating orthopoxvirusinfections and/or eczema vaccinatum comprising oral administration to asubject in need thereof the above mentioned formulation. Typically, theformulation of the present invention is administered in an amount suchthat the dose of ST-246 is 200 mg to 2000 mg per day, preferably 400 mgto 2000 mg per day, and most preferably 600 mg to 1200 mg daily. Dosageis typically adjusted according to body weight, particularly inpediatric populations.

Additionally, the present invention also provides a process of makingthe dry suspension which involves mixing ST-246 or ST-246 granulatedpowder with simethicone.

Optionally, at least one suspending agent, at least one lubricant, atleast one excipient, at least one further anti-foaming agent, at leastone sweetener and/or at least one flavoring may be mixed with the ST-246and the simethicone.

Advantageously, mixing is carried out using geometric mixing.

Finally, the present invention provides a method of making the abovementioned formulation wherein the dry suspension is dispersed in water,and wherein the water advantageously contains a suspending agent asherein described above.

As used herein. “percent,” “percentage” or the symbol “%” means thepercent of the component indicated in the composition based on theamount of the carrier present in the composition, on a weight/weight(w/w), weight/volume (w/v) or volume/volume (v/v) concentration, asindicated with respect to any particular component, all based on theamount of the carrier present in the composition. Thus, different typesof carriers can be present in an amount of up to 100% as indicated,which does not preclude the presence of the API, the amount of which canbe indicated as a % or as a certain number of mg present in thecomposition or a certain number of mg/mL present, where the % or mg/mLis based on the amount of the total carrier present in the composition.Certain types of carriers can be present in combination to make up 100%of the carrier.

As used herein, the terms “Tecovirimat” and “ST-246” refer to thecompound4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2-(1H)-yl)-benzamide.

The invention is further described by the examples given below.

EXAMPLES Example 1. Production of a Dry Suspension ContainingTecrovirmat Monohydrate (ST-246) for Reconstitution, 200 mg

A stable oral powder containing ST-246 was prepared, particularly forpediatric and % or geriatric application. The development of the powderinvolved the following stages;

-   -   1. Formulation and evaluation of various dry suspensions.    -   2. Optimization and evaluation of various level of anti-foaming        agents and lubricant and their effect on product properties.    -   3. Optimization and evaluation of blending time and lubrication        time in the product manufacturing process and its effect on        product properties.    -   4. Manufacture of batches for stability studies.        Materials: The Following Materials were Used.

S. # .Material Supplier/Lot# 1 Tecovirimat Monohydrate, micronized, SigaTechnologies for discriminatory dissolution method Lot # SG-10C12-T1039development (Trial #2, d90 = 21.51 μm) 2 Tecovirimat Monohydrate,micronized, Siga Technologies for discriminatory dissolution method Lot# SG-10C12-T1039 development (Trial #3, d90 = 38.74 μm) 3 TecovirimatMonohydrate, micronized, Siga Technologies for discriminatorydissolution method Lot# SG-10C12-T1039 development (Trial #4, d90 =81.53 μm) 4 Tecovirimat Granulate Siga Technologies Lot # 1302679 5Tecovirimat Granulate Siga Technologies Lot # 1401165 6 Colloidalsilicon dioxide, NF Cabot (Cabosil MSP) Lot #1222272 7 Croscarmellosesodium, NF FMC Biopolymer (AcDiSol) Lot # TN12824921 8 Lactosemonohydrate, NF DFE (SuperTab11SD) Lot # 10705838 9 Lactose monohydrate,NF DFE (SuperTab11SD) Lot # 10700181 10 Lactose monohydrate, NF DFE(SuperTab11SD) Lot # 10737298 11 Microcrystalline cellulose, NF FMCBiopolymer (Avicel PII101) Lot # P113825526 12 Ilypromellose, USP Dow(Methocel E3 LV Premium) Lot # 1D020124L1 13 Sodium lauryl sulfate, NFSpectrum Lot # 1DB0596 14 Purified Water, USP Ricca Chemicals Lot #4409016 15 Sucralose, NF Spectrum Lot # 1CF0697 16 Sucralose, NFSpectrum Lot # 1DF0586 17 Strawberry flavor, #133.16296 Bell Flavors 18Black cherry nat type flavor Kerry Lot # 260314 19 Simethicone, USPNusil Technologies (MED-340, simethicone content 100%) Lot # 63865 20Simethicone Granular Solid, USP Nusil Technologies (MED-342, simethiconecontent 30'%) Lot # 63775 21 Simethicone Granular Solid, USP NusilTechnologies (MED-342, simethicone content 30%) Lot # 66777 27Simethicone Granular Solid, USP Nusil Technologies (MED-342, simethiconecontent 30%) Lot # 67719 23 Magnesium stearate, NF Mallinckrodt (HyQual)Lot # 1301000109 24 Crospovidone, USP/NF BASF (Kollidon CL-M) Lot #10204988Q0 25 Povidone, USP/NF BASF (Kollidon 12PF) Lot # 12714424U0 26Povidone, USP/NF BASF (Koi Udon, 90F) Lot # 45877768E0 27 HypromelloseDow (Methocel F50) Lot # 2L03012N21 28 Hypromellose Dow (Methocel E50)Lot # 2C01012N23 29 Methylcellulose, USP Dow (Methocel A4M Premium) Lot# 2E19012N11 30 Methylcellulose, 400 cps, USP Spectrum Lot # 2CJ0081 31Methylcellulose, 400 cps, USP Spectrum Lot # 2DC0205 32 Methylcellulose,15 cps, USP Spectrum Lot # 2DE0263 33 Hydroxypropyl cellulose, NFAshland (Klucel JF Pharm) Lot # 38296 34 Hydroxypropyl cellulose, NFAshland (Klucel JXF Pharm) Lot # 40289 35 Hydroxypropyl cellulose, NFAshland (Klucel HF Pharm) Lot # 49264 36 Hydroxypropyl cellulose, NFAshland (Khtcel MF Pharnt) Lot # 38949 37 Hydroxylethyl cellulose, NFAshland (Natrosol 250L Pharm) Lot # J1967 38 Carrageenan, NF FMCBiopolymer (Gelcarin GP3 79) Lot # 50218031 39 Carrageenan, NF FMCBiopolymer (SeaSpen PF) Lot # 20226021 40 Microcrystalline Cellulose andSodium FMC Biopolymer Carboxymethylcellulose, NF Lot # B1204C (AvicelRC-581) 41 Microcrystalline Cellulose and Sodium FMC BiopolymerCarboxymethylcellulose, NF Lot # EN13825521 (Avicel CL-611) 42Microcrystalline Cellulose and Sodium FMC BiopolymerCarboxymethylcellulose, NF Lot # DN13825459 (Avicel RC-591) 43 SodiumAlginate, USP/NF FMC Biopolymer (Protanal LFR5/60) Lot # H191208 44Xanthan gum, USP/NF CP Kelco (Xantural 75) Lot # 2B4685K 45 Simethicone50% Powder AIC Lot # 4060-50205

Two typical dry suspensions are shown in Table. The dry suspensionsaccording to the present invention contain granules of ST-246 andadditional excipients to improve taste suspendability, texture andfavor.

TABLE 1 Compo- Compo- sition of sition of Formulation Formulation No.Ingredient DS83 (mg) DS84 (mg) 1 Tecovirimat granulate 346.5 346.5 2Lactose monohydrate (SuperTab 93.0 0.0 11SD, DMV Fonterra Excipients) 3Klucel JF Pharm (Ashland) 125.0 118.0 4 Sucralose, USP 10.0 10.0 5Flavor, black cherry (Virginia Dare, 3.0 3.0 #23950) 6 Simethiconegranular solid (NuSil 20.0 20.0 MED-342) 7 Magnesium stearate 2.5 2.5Total 600.0 500.0

Example 2: Development of the Dry Suspensions for Reconstitution, 200 mg

The composition of the Tecovirimat granulate is shown in Table 2. Anoral powder for suspension using a suspending agent containingmicrocrystalline cellulose and sodium carboxymethylcellulose (AvicelCL-611) was used as a Target formulation is shown in Table 3. The targetformulation exhibits good physical properties. However, the xanthan gumwhich is co-processed along with microcrystalline cellulose results incoagulation behavior during the dissolution tests due to the interactionwith the surfactant used in the dissolution medium and thus poor drugrelease.

TABLE 2 Composition of ST-246 commercial granules Quantity per Unit S.No Ingredients (mg) 7 ST-246, Monohydrate, micronized 209.00Microcrystalline Cellulose, NF (Avicel PH101) 49.628 3 LactoseMonohydrate, NF (Supertab 11SD) 33.15 4 Croscarmellose Sodium. NF(Ac-di-sol SD-711) 31.2 5 Colloidal Silicone Dioxide, NF (Cab-O-Sil ®1.95 M5P) 6 Hypromellose, USP (Methocel E3) 13.65 7 Sodium LaurylSulfate, NF 7.80 8 Purified Water*, USP q.s. Total 346.4 *water isremoved during drying

TABLE 3 ST-246 oral powder for suspension (Target Formulation) Prototype1 Prototype 2 (mg per (mg per Ingredient dose) dose) ST-246, granulate346.5 346.5 Lactose monohydrate (SuperTab 11SD, DMV 503.3 505.1 FonterraExcipients) Simethicone granular solid, (NuSil MED-342) 10.0 10.0 AvicclCL-611, NF (FMC BioPolymer) 125.0 125.0 Sucralose, USP 10.0 10.0 Flavor,strawberry (Kerry Item: U1-721636) 5.0 — Flavor, black cherry (KerryItem: U1-717664) — 3.0 FD&C Red #3 0.10 — FD&C red #40 55 0.3Methylparaben, NF 0.08 0.08 Propylparaben, NF 0.02 0.02 Total 1,000.01,000.0

Example 3: Screening and Selection of Suspending Agent

ST-246 granules prepared for capsule dosage form were used for thepreparation of ST-246 oral powder for reconstitution, 200 mg. Toevaluate the suspendability of the granules in various suspendingagents, various suspending agents were dispersed in 50 mL purified water(Table 4). Concentrations of suspending agents in formulations DS-1 toDS-16 were produced according to the maximum potential from FDA InactiveIngredient Guide (IIG). A placebo was prepared and compared visuallywith the target formulation and the concentration of suspending agentwas adjusted accordingly in formulation DS-17 to DS-38

TABLE 4 Composition and Observation of Suspending Agent PlaceboSolutions/Suspensions. Consistency (Visual observation in Polymercomparison Viscosity quantity with target (cps, target equilvalent toformulation formulation Brand Formulation 10 doses Disperse Overnightviscosity viscosity Chemicals name ID (concentration) Appearance speedsedimentation +++++) 50-100 cps) Crospovidone Kollidon DS-1 2.500 gwhite fast sedimentation, less viscous not CL-M (5%, w/v) suspensioneasy to ++ measured redisperse by shaking Povidone (PVP) Kollidon DS-20.750 g colorless fast none less viscous not 90 F (1.5 %, w/v)solution + measured DS-17 1.500 g colorless fast none less viscous not(3%, w/v) solution + measured DS-29 3.000 g colorless fast nonecomparable 55.8 (6%, w/v) solution ++++ Kollidon DS-3 0.750 g colorlessfast none less viscous not 12 PF (1.5%, w/v) solution + measured DS-181.500 g colorless fast none less viscous not (3%, w/v) solution +measured DS-30 3.000 g colorless fast none less viscous not (6%, w/v)solution ++ measured Hypromellose Methocel DS-4 1.500 g colorless slownone comparable 43.1 (HPMC) F50 (3%, w/v) solution +++++ Methocel DS-51.500 g colorless slow none comparable 85.6 E50 (3%, w/v) solution +++++DS-19 0.750 g colorless slow none less viscous not (1.5%, w/v) solution++ measured Methylcellulose Methocel DS-6 0.595 g colorless slow nonemore not (MC) A4MP (1.19%, w/v) solution viscous measured ++++++ DS-260.250 g colorless slow none comparable 24.9 (0.5%, w/v) solution ++++Methyl DS-7 0.595 g colorless slow none comparable not cellulose,(1.19%, w/v) solution +++++ measured 400 cps DS-27 0.250 g colorlessslow none comparable 17.1 (0.5%, w/v) solution ++++ Hydroxypropyl KlucelDS-8 3.350 g colorless slow none more not cellulose (HPC) JF Pharm(6.7%, w/v) solution viscous measured +++++++ DS-20 0.750 g colorlessslow none less viscous not (1.5%, w/v) solution ++ measured DS-31 1.500g colorless slow none comparable 20.4 (3%, w/v) solution ++++ KlucelDS-9 3.350 g colorless slow none more not HF (6.7%, w/v) gel viscous,gel, measured Pharm high viscosity DS-21 0.500 g colorless slow nonemore not (1.0%, w/v) solution viscous measured ++++++++ DS-33 0.375 gcolorless slow none comparable 123.9  (0.75%, w/v) solution ++++++Klucel DS-10 3.350 g colorless slow none more not MF (6.7%, w/v) gelviscous, gel, measured Pharm high viscosity DS-22 0.500 g colorless slownone more not (1.0%, w/v) solution viscous measured +++++++ DS-34 0.375g colorless slow none comparable 71.0 (0.75%, w/v) soluton +++++Hydroxyethyl Natrosol DS-11 1.500 g yellowish fast none comparable 14.9cellulose (HEC) 250L (3%, w/v) solution ++++ Pharm DS-28 2.000 gyellowish fast none comparable not (4%, w/v) solution ++++ measuredCarrageenan Gelcarin DS-12 0.750 g yellowish slow none more not GP379(1.5%, w/v) gel viscous, gel, measured high viscosity DS-23 0.200 gyellowish slow none comparable 65.5 (0.4%, w/v) solution +++++ SeaSpenDS-13 0.750 g milky slow none more not PF (1.5%, w/v) gel viscous, gel,measured high viscosity DS-24 0.200 g milky slow none comparable 20.1(0.4%, w/v) solution ++++++ Microcrystalline Avicel DS-14 1.500 g whitefast none more not cellulose/sodium RC-581 (3%, w/v) suspension viscousmeasured carboxymethyl +++++++ cellulose DS-35 1.250 g white fast nonecomparable 84.3 (MCC/CMCNa) (2.5%, w/v) suspension ++++++ Avicel DS-151.500 g white fast none more not CL-611 (3%, w/v) suspension viscousmeasured +++++++ DS-36 1.250 g white fast none comparable 35.4 (2.5%,w/v) suspension +++++ Avicel DS-37 1.250 g white fast none comparable93.8 RC-591 (2.5%, w/v) suspension ++++++ Sodium Protanal DS-16 0.062 gcolorless fast none less viscous not Alginate LFR (0.123%, w/v)solution + measured 5/60 DS-25 0.800 g yellowish slow none less viscousnot (1.6%, w/v) solution ++ measured DS-32 1.600 g yellowish slow noneless viscous not (3.2%, w/v) solution ++++ measured DS-38 2.000 gyellowish slow none comparable 32.4 (4%, w/v) solution +++++

Povidone (Kollidon 90 F) 6%, Hypromellose (Methocel F 50 and E50) 3%,Methylcellulose (Methocel A4MP), Methyl Cellulose 400 cps 0.5%,Hydroxypropyl cellulose (Klucel HF and MF) 0.75%, Hydroxy EthylCellulose (Natrosol 250 L Pharm) 3%, Avicel RC-581—2.5%. AvicelRC-591—2.5% and Sodium alginate 4% show comparable viscosity to theTarget formulation containing Avicel CL-611.

The suspending agent concentrations with comparable consistency to thatof the Target formulation (containing Avicel CL-611 as suspending agent)were selected as the formulation viscosity modifier.

Example 4: Formulation of Suspensions by Mixing ST-246 Granules withFormulation Vehicles

To evaluate the suspendability of ST-246, ingredients such as sucralose,simethicone (adsorbed on lactose monohydrate) and suspension polymerswere added. Lactose monohydrate was added to make up the weight of thecomposition. These ingredients were mixed with the selected suspendingagent vehicle concentration from Example 3. The resultant compositionsare given in Table 5.

The formulation procedure included:

-   -   1. Adsorbing 1 g of simethicone (MED-340, liquid) on 19 g        lactose monohydrate (SuperTab 11SD).    -   2. Geometric mixing of the ST-246 granules, sucralose,        simethicone adsorbed on lactose, and lactose monohydrate to make        5 g (5 doses) blends considering the quantity of polymer        quantity sufficient (Q.S.) to 25 mL of vehicle.    -   3. Dispersing the blend in Q.S. to 25 mL of formulation vehicle        prepared in Example 3.    -   4. Evaluation of the sedimentation, redispersibility, and pH of        the suspensions.    -   5. Transfer of each of about 5 mL of suspension in screw cap        glass vials, to store the samples at room temperature, at 2 to        8° C. and at 40° C./75% RH for 14 Days and recording the        observations. Table 6 shows the results of physical properties        of suspensions.

TABLE 5 Composition of suspensions-Suspending Agent Selection Quantity(g) Equivalent to 5 doses S.# Ingredients DS-39 DS-40 DS-41 DS-42 DS-43DS-44 DS-45 DS-46 1 ST-246 Granules 1.733 1.733 1.733 1.733 1.733 1.7331.733 1.733 2 Sucralose, NF 0.050 0.050 0.050 0.050 0.050 0.050 0.0500.050 3 Simethicone, USP (MED-340) 0.025 0.025 0.025 0.025 0.025 0.0250.025 0.025 Lactose Monohydrate, NF, 0.475 0.475 0.475 0.475 0.475 0.4750.475 0.475 (SuperTab 11SD) 5 Lactose Monohydrate, NF 1.967 1967 1.9672.617 2.617 2.592 2.592 1.217 (SuperTab 11SD) 6 Hypromellose (Methocel F50), 25.750 — — — — — — — 3% Dispersion Hypromellose (Methocel E 50), —25.750 — — — — — — 3% Dispersion Hydroxyethyl cellulose — — 25.750 — — —— — (Natrosol 250L), 3% Dispersion Carrageenan (Iota) (Gelcarin GP379),— — — 25.100 — — — — 0.4% Dispersion Carrageenan (Iota) (SeaSpen PF), —— — — 25.100 — — — 0.4% Dispersion Methyl Cellulose (Methocel A4MP), — —— — — 25.125 — — 0.5% Dispersion Methyl Cellulose, 400 cps, 0.5%Dispersion — — — — — — 25.125 — Povidone (Kollidon 90F), 6% Dispersion —— — — — — — 26.500 Hydroxypropyl cellulose (Klucel JF Pharm), — — — — —— — — 3% Dispersion Hydroxypropyl cellulose (Klucel HF Pharm), — — — — —— — — 0.75% Dispersion Hydroxypropyl cellulose (Klucel MF Pharm), — — —— — — — — 0.75% Dispersion Microcrystalline cellulose and carboxymethyl— — — — — — — — cellulose (Avicel RC-581), 2.5% DispersionMicrocrystalline cellulose and carboxymethyl — — — — — — — — cellulose(Avicel CL-611), 2.5% Dispersion Microcrystalline cellulose andcarboxymethyl — — — — — — — — cellulose (Avicel RC-591), 2.5% DispersionSodium Alginate (Protanal LFR 5/60), — — — — — — — — 4% Dispersion S.#Ingredients DS-47 DS-48 DS-49 DS-50 DS-51 DS-52 DS-53 1 ST-246 Granules1.733 1.733 1.733 1.733 1.733 1.733 1.733 2 Sucralose, NF 0.050 0.0500.050 0.050 0.050 0.050 0.050 3 Simethicone, USP (MED-340) 0.025 0.0250.025 0.625 0.025 0.025 0.025 Lactose Monohydrate, NF, 0.475 0.475 0.4750.475 0.475 0.475 0.473 (SuperTab 11SD) 5 Lactose Monohydrate, NF 1.9672.530 2.530 2.092 2.092 2.092 1.717 (SuperTab 11SD) 6 Hypromellose(Methocel F 50), — — — — — — — 3% Dispersion Hypromellose (Methocel E50), — — — — — — — 3% Dispersion Hydroxyethyl cellulose — — — — — — —(Natrosol 250L), 3% Dispersion Carrageenan (Iota) (Gelcarin GP379), — —— — — — — 0.4% Dispersion Carrageenan (Iota) (SeaSpen PF), — — — — — — —0.4% Dispersion Methyl Cellulose (Methocel A4MP), — — — — — — — 0.5%Dispersion Methyl Cellulose, 400 cps, 0.5% Dispersion — — — — — — —Povidone (Kollidon 90F), 6% Dispersion — — — — — — Hydroxypropylcellulose (Klucel JF Pharm), 25.750 — — — — — — 3% DispersionHydroxypropyl cellulose (Klucel HF Pharm), — 25.187 — — — — — 0.75%Dispersion Hydroxypropyl cellulose (Klucel MF Pharm), — — 25.187 — — — —0.75% Dispersion Microcrystalline cellulose and carboxymethyl — — —25.625 — — — cellulose (Avicel RC-581), 2.5% Dispersion Microcrystallinecellulose and carboxymethyl — — — — 25.625 — — cellulose (AvicelCL-611), 2.5% Dispersion Microcrystalline cellulose and carboxymethyl —— — — — 25.625 — cellulose (Avicel RC-591), 2.5% Dispersion SodiumAlginate (Protanal LFR 5/60), — — — — — — 26.000 4% Dispersion

The sedimentation coefficients were determined by measuring the heightof the suspension in a 40 cc vial divided by the height of the sedimentin a vial. Sedimentation coefficient versus time is used as an indicatoras to the stability of suspension over the time.

The redispersibility was evaluated by centrifuging the suspension inEppendorf tube at 5000 rpm for 10 minutes followed by shaking manuallyor with wrist action shaker, if the sediment in centrifuge suspendedagain, it was recorded as “redispersible.”

TABLE 6 Characterization of Physical Stability of Selected FormulationsDS-39 DS-40 DS-41 DS-42 D5-43 DS-44 DS-45 DS-46 Methocel MethocelNatrosol Gelcarin SeaSpen Methocel MC, Kollidon F50 E50 250L GP379 PFA4MP 400 cps 90F Formulation ID 3% 3% 3% 0.4% 0.4% 0.5% 0.5% 6% Polymerw/v w/v w/v w/v w/v w/v w/v w/v Observations 1 Appearance White WhiteWhite White White White White White dispersion dispersion dispersiondispersion dispersion dispersion dispersion dispersion 2 Sedimentation100 100 1.00 1.00 1.00 1.00 1.00 1.00 Coeff (10 min) 3 Sedimentation1.00 1.00 1.00 1 00 1.00 1.00 1.00 1.00 Coeff (30 min) 4 Sedimentation1.00 1.00 0.72 0.46 1.00 1.00 1.00 0.51 Coeff (12 h) 5 Sedimentation 1001.00 0.58 0.38 1.00 1.00 0.92 0.41 Coeff (24 h) 6 Observation None NoneNone None None Noite None None at the time of mixing the solids with theformulation vehicle 7 Redispersibility No No Redispersible RedispersibleNo No Redispersible Redispersible after 24 hours sedimentationsedimentation sedimentation sedimentation (gentle shaking) 8 pH 5.625.81 5.57 5.30 6.67 5.71 5.78 5.67 Stability: 2-8° C. for 14 days 1Appearance white white white white white white white white (Color) 2Signs of two two almost clear uni- two two clear Creaming, layers layersclear supernatant form layers layers supernatant flocculationsupernatant 3 Sedimentation 0.98 0.99 0.34 0.34 0.97 0.97 0.95 0.31Coeff 4 Redispersibility redispersible redispersible redispersibleredispersible redispersible redispersible redispersible redispersibleStability: 40° C./75% RH for 14 days 1 Appearance white white whitewhite white white white white (Color) 2 Signs of two two clear clearclear clear clear clear Creaming, layers layers supernatant supernatantsupernatant supernatant supernatant supernatant flocculationsedimentation sedimentation two two layers layers 3 Sedimentation 0.970.98 0.34 0 37 0.34 0.52 0.56 0.34 Coeff 4 Redispersibilityredispersible redispersible redispersible redispersible redispersibleredispersible redispersible redispersible Stability: Room temperaturefor 14 days 1 Appearance white white white white white white while white(Color) 2 Signs of two two clear clear clear two two opaque Creaming,layers layers supernatant supernatant supernatant layers layerssupernatant flocculation Sedimentation 0.98 0.97 0.30 0.32 0.76 0.650.94 0.30 Coeff 4 Redispersibility redispersible redispersibleredispersible redispersible redispersible redispersible redispersibleredispersible 5 pH 5.62 5.58 5.49 5.25 6.77 5.65 5.66 5.44 DS-47 DS-48DS.49 DS-50 DS-51 DS-52 DS-53 Klucel Klucel Klucel Avicel Avicel AvicelProtanal Formulation ID JF HF MF RC-581 CL-611 RC-591 LFR5/60 Polymer 3%w/v 0.75% w/v 0.75% w/v 2.5% w/v 2.5% w/v 2.5% w/v 4% w/v Observations 1Appearance White White White White White White White dispersiondispersion dispersion dispersion dispersion dispersion dispersion 2Sedimentation 1.00 1.00 1.00 1.00 1.00 1.00 1.00 Coeff (10 min) 3Sedimentation 1.00 1.00 1.00 1.00 1.00 1.00 1.00 Coeff (30 min) 4Sedimentation 1.00 1.00 1.00 1.00 1.00 1.00 0.27 Coeff (12 h) 5Sedimentation 1.00 1.00 1.00 1.00 1.00 1.00 0.23 Coeff (24 h) 6Observation Thickening Thickening Thickening None None None Thinning ofat the time of of of formulation of mixing formulation formulation,formulation, after the solids gel gel overnight with the standingformulation vehicle 7 Redispersibility No No No No No No Redispersibleafter 24 hours sedimentation sedimentation sedimentation sedimentationsedimentation sedimentation but (gentle shaking) agglomerates 8 pH 5.76Not Not 5.58 5.56 5.57 5.16 checked checked Stability: 2-8° C. for 14days 1 Appearance white Not Not while white white white (Color) checkedchecked 2 Signs of two layers creamy, uniform creamy clear Creaming,phase supernatant flocculation separation 3 Sedimentation 0.98 0.83 1.001.00 0.21 Coeff 4 Redispersibility redispersible redispersibleredispersible redispersible redispersible Stability: 40° C./75% RH for14 days 1 Appearance white Not Not white white white white (Color)checked checked 2 Signs of a thin creamy, uniform creamy clear Creaming,clear phase supernatant flocculation supernatant, separation a thickflocculation layer 3 Sedimentation 0.59 0.78 1.00 1.00 0.34 Coeff 4Redispersibility redispersible redispersible redispersible redispersibleredispersible redispersible redispersible Stability: Room temperaturefor 14 days 1 Appearance white white white white white white white(Color) 2 Signs of opaque very very creamy, uniform uniform clearCreaming, supernatant viscous gel viscous gel phase supernatantflocculation separation 3 Sedimentation 0.42 1.00 1.00 0.84 1.00 1.000.33 Coeff 4 Redispersibility redispersible redispersible redispersibleredispersible redispersible redispersible redispersible 5 pH 5.49 4.745.65 5.53 5.49 5.50 5.14

Suspensions were prepared using 3% Methocel F50, 3% Methocel E50, 0.5%Methocel A4MP, 0.5% Methylcellulose 400 cps, or 3% Klucel JF assuspending agents and showed comparable physical properties as theTarget formulation using 2.5% Avicel CL-611 as a vehicle, and alsoshowed comparable results of physical stability when stored at 2 to 8°C., room temperature and at 40° C./75% RH for the reconstitution study.

Example 5: Formulation and Evaluation of Powders for ReconstitutionUsing Selected Polymers

Solid blends (including suspending agents selected in Example 4) wereformulated, and the rates of reconstitution (hydration time) in waterwere evaluated. Compositions are given in Table 7.

TABLE 7 Composition of solid blends (including suspending agents) forreconstitution (40 mg/ml). Quantity per unit (mg) S.# Ingredients DS-54DS-55 DS-56 DS-57 DS-58 1 ST-246 Granules* 346.50 346.50 346.50 346.50346.50 2 Sucralose, NF 10.00 10.00 10.00 10.00 10.00 3 Simethicone, USP5.00 5.00 5.00 5.00 5.00 (MED-340) 4 Lactose 95.00 95.00 95.00 95.0095.00 Monohydrate, NF (SuperTab 11SD) 5 Lactose 393.50 393.50 518.50518.50 393.50 Monohydrate, NF (SuperTab 11SD) 6 Hypromellose 150.00 — —— — (Methocel F50) Hypromellose — 150.00 — — — (Methocel E50) MethylCellulose — — 25.00 — — (Methocel A4MP), USP Methyl Cellulose, — — —25.00 — 400 cps, USP Hydroxypropyl — — — — 150.00 cellulose (Klucel JFPharm), NF 7 Purified water, — — — — — USP, Q.S. to 5 mL Total 1000.001000.00 1000.00 1000.00 1000.00 *granules equivalent to 200 mgTecovirimat

The formulation procedure was as follows;

-   -   1. Adsorbing of 1 g of simethicone (MED-340, liquid) on 19 g        lactose monohydrate (SuperTab 11SD)    -   2. Geometric mixing of Tecovirimat granules, sucralose, and        simethicone adsorbed lactose, then weighing of quantity        equivalent to 10 units of blend and then geometric mixing with        other components for each formulation;    -   3. Dispersing of the blend in purified water to make Q.S. to 50        mL;    -   4. Observing the rate of reconstitution, sedimentation,        redispersibility, and pH of the suspensions (see Table 8);    -   5. Storing the samples at room temperature, at 2 to 8° C. and at        40° C./75% RH for 14 Days and recording the observations (see        Table 9);    -   6. Conducting a freeze-thawing cycle of 3-day—10° C. and 3-day        room temperature and repeating 5 times and recording the        observations (see Table 10 and 11).

TABLE 8 Observation of reconstitution and 1-day sedimentation of DS-54to DS-58 DS-54 DS-55 DS-56 DS-57 DS-58 Formulation ID Methocel F50Methocel E50 Methocel A4MP MC, 400 cps Klucel JF Polymer 3% w/v 3% w/v0.5% w/v 0.5% w/v 3% w/v Observations T = 0, room temperature 1 Time for7 7 1 1 2 reconstitution (min) 2 Observation for Still chunks Stillchunks No chunks No chunks Small chunks reconstitution remaining atremaining at remaining, remaining, remaining at bottom after bottomafter easy to easy to bottom after shaking shaking disperse disperseshaking 3 Appearance (visual) white, uniform white, uniform white,uniform white, uniform white, uniform 4 pH 5.76 5.81 5.86 5.89 5.78 5Particle size (μm) 3.20 ± 2.56 3.03 ± 1.91 3.85 ± 3.11 3.3 1 ± 2.43 3.86± 3.31 6 Forced settling and redispersible redispersible redispersibleredispersible redispersible Redispersibility Observations T = 30 min,room temperature 1 Sedimentation Coefficient 1.00 1.00 1.00 1.00 1.00 2Appearance (visual) white, uniform white, uniform white, uniform white,uniform white, uniform 3 Redispersibility redispersible redispersibleredispersible redispersible redispersible Observations T = 1 hr, roomtemperature 1 Sedimentation Coefficient 1.00 1.00 1.00 1.00 1.00 2Appearance (visual) white, uniform white, uniform white, uniform white,uniform white, uniform 3 Redispersibility redispersible redispersibleredispersible redispersible redispersible Observations T = 24 hr, roomtemperature 1 Sedimentation Coefficient 1.00 1.00 1.00 0.98 0.95 2Appearance (visual) white, uniform white, uniform two layers two layersopaque supernatant with floccules 3 Redispersibility redispersibleredispersible redispersible redispersible redispersible

TABLE 9 14-Days stability of DS-54 to DS-58 DS-54 DS-55 DS-56 DS-57DS-58 Formulation ID Methocel F50 Methocel E50 Methocel A4MP MC, 400 cpsKlucel JR Polymer 3% w/v 3% w/v 0.5% w/v 0.5% w/v 3% w/v Observations T= 7 days, room temperature 1 Sedimentation 0.95 0.97 0.95 0.96 0.65Coefficient 2 Appearance two layers two layers two layers two layersopaque (visual) supernatant with floccules 3 Redispersibilityredispersible redispersible redispersible redispersible redispersible 4pH 5.72 5.79 5.77 5.78 5.70 5 Particle 3.33 ± 2.67 3.37 ± 2.29 3.11 ±1.88 3.37 ± 1.96 3.20 ± 2.13 size (μm) Observations T = 7 days, 2-8° C.1 Sedimentation 0.97 0.97 0.98 0.99 0.87 Coefficient 2 Appearance twolayers two layers two layers two layers opaque (visual) supernatant withfloccules 3 Redispersibility redispersible redispersible redispersibleredispersible redispersible 4 pH 5.75 5.82 5.81 5.79 5.75 5 Particle3.13 ± 2.18 3.20 ± 2.30 3.51 ± 2.37 3.37 ± 2.08 3.57 ± 2.52 size (μm)Observations T = 7 days, 40° C./75% RH l Sedimentation 0.35 0.43 0.440.41 0.81 Coefficient 2 Appearance milky opaque clear opaque opaque(visual) supernatant supernatant supernatant supernatant supernatantwith with floccules floccules 3 Redispersibility redispersibleredispersible redispersible redispersible redispersible 4 pH 5.48 5.555.53 5.57 5.44 5 Particle 3.51 ± 2.49 3.45 ± 2.54 3.86 ± 2.55 3.96 ±3.10 3.81 ± 2.37 size (μm) Observations T = 14 days, room temperature 1Sedimentation 0.96 0.96 0.49 0.96 0.69 Coefficient 2 Appearance twolayers two layers two layers, two layers opaque (visual) clearsupernatant supernatant with with floccules floccules 3 Redispersibilityredispersible redispersible redispersible; redispersible redispersiblesedimentation occurs at 30 min after shaking 4 pH 5.68 5.69 5.72 5.715.64 5 Particle 3.69 ± 2.45 3.54 ± 2.68 13.51 ± 2.78 3.68 ± 2.95 3.48 ±2.66 size (μm) Observations T = 14 days, 2-8° C. 1 Sedimentation 0.960.96 0.96 0.95 0.90 Coefficient 2 Appearance two layers two layers twolayers two layers opaque (visual) supernatant with floccules 3Redispersibility redispersible redispersible redispersible redispersibleredispersible 4 pH 5.74 5.75 5.75 5.78 5.76 5 Particle 3.86 ± 2.86 3.57± 2.44 3.46 ± 2.58 3.76 ± 2.74 3.78 ± 2.68 size (μm) Observations T = 14days, 40° C./75% RH 1 Sedimentation 0.74 0.78 0.39 0.33 0.60 Coefficient2 Appearance clear clear clear clear clear (visual) supernatantsupernatant supernatant supernatant supernatant with with with with withfloccules floccules floccules, floccules, floccules, an opaque an opaquean opaque flocculation flocculation flocculation layer between layerbetween layer between clear clear clear supernatant supernatantsupernatant and and and sedimentation sedimentation sedimentation 3Redispersibility redispersible redispersible redispersible;redispersible; redispersible curdy, loose curdy, loose sedimentationsedimentation right right away after away after shaking shaking 4 pH5.32 5.32 5.40 5.40 5.32 5 Particle 3.93 ± 3.00 3.86 ± 3.08 3.94 ± 3.033.96 ± 3.10 3.83 ± 2.72 size (μm)

TABLE 10 Observations for freeze-thawing cycles of −10° C. (3-day) andRT (3-day) DS-54 DS-55 DS-56 DS-57 DS-58 Formulation ID Methocel F50Methocel E50 Methocel A4MP MC, 400 cps Klucel JF Polymer 3% w/v 3% w/v0.5% w/v 0.5%. w/v 3% w/v Observations after Freeze-Thawing Cycle:storage at −10° C. for 3 days followed by at RT for 3 days Sedimentation1 Cycle 0.96 0.96 0.48 0.34 0.66 Coefficient 2 Cycle 0.96 0.96 0.50 0.340.67 3 Cycle 0.96 0.96 0.50 0.34 0.54 4 Cycle 0.96 0.96 0.49 0.30 0.70 5Cycle 0.96 0.96 0.49 0.38 0.79 Appearance (visual) 1 Cycle uniformuniform clear supernatant sedimentation opaque with floccules, twolayers, supernatant a thin opaque opaque with floccules flocculationlayer supernatant between clear with floccules supernatant andsedimentation 2 Cycle sedimentation uniform clear sedimentation opaquetwo layers supernatant two layers, supernatant opaque with flocculessupernatant with floccules 3 Cycle sedimentation uniform clearsupernatant, opaque to clear A thin clear two layers sedimentationsupernatant, supernatant two layers sedimentation on top, a two layersthick opaque flocculation layer between clear supernatant andsedimentation 4 Cycle uniform uniform clear clear supernatant, opaquesupernatant a milky supernatant flocculation with floccules layerbetween clear supernatant and sedimentation 5 Cycle uniform uniformclear clear supernatant, opaque supernatant a milky supernatantflocculation with floccules layer between clear supernatant andsedimentation, sedimentation two layers Redispersibility 1 Cycleredispersible redispersible redispersible; redispersible redispersiblesedimentation occurs at 10 min after shaking 2 Cycle redispersibleredispersible redispersible; redispersible redispersible sedimentationoccurs at 10 min after shaking 3 Cycle redispersible redispersibleredispersible; redispersible; redispersible sedimentation sedimentationoccurs at 10 min occurs at 10 min alter shaking, after shakingsedimentation appears loose and curdy 4 Cycle redispersibleredispersible redispersible: redispersible; redispersible sedimentationsedimentation occurs at 10 min occurs at 10 min after shaking, aftershaking sedimentation appears loose and curdy 5 Cycle redispersibleredispersible redispersible; redispersible; redispersible sedimentationsedimentation occurs at 10 min occurs at 10 min after shaking, aftershaking sedimentation appears loose and curdy pH 1 Cycle 5.66 5.66 5.695.70 5.64 2 Cycle 5.62 5.63 5.66 5.69 5.57 3 Cycle 5.60 5.58 5.62 5.665.52 4 Cycle 5.61 5.56 5.60 5.61 5.54 5 Cycle 5.65 5.67 5.62 5.59 5.50Particle 1 Cycle 3.89 ± 3.33 3.88 ± 3.21 3.86 ± 2.81 3.92 ± 3.20 3.82 ±2.46 size 2 Cycle 3.94 ± 2.87 3.98 ± 2.97 3.97 ± 3.09 4.05 ± 3.25 3.99 ±2.87 (μm) 3 Cycle 4.02 ± 3.25 4.08 ± 3.83 4.12 ± 3.15 4.06 ± 3.09 4.07 ±3.69 4 Cycle 4.21 ± 3.07 4.27 ± 3.01 4.26 ± 3.29 4.25 ± 2.78 4.26 ± 2.865 Cycle 4.31 ± 3.04 4.29 ± 2.85 4.28 ± 2.99 4.32 ± 3.32 4.30 ± 3.30

TABLE 11 Observations for Freeze-Thaw cycles of RT (3-day) and 2-8° C.(3-day) DS-54 DS-55 DS-56 DS-57 DS-58 Formulation ID Methocel F50Methocel E50 Methocel A4MP MC. 400 cps Klucel JF Polymer 3% w/v 3% w/v0.5% w/v 0.5% w/v 3% w/v Observations after Thawing-freeze Cycle:storage at RT for 3 days followed by at 2-8° C. for 3 days SedimentationCoellicient 1 Cycle 0.97 0.97 0.53 0.96 0.62 2 Cycle 0.96 0.96 0.55 0.240.77 3 Cycle 0.96 0.96 0.53 0.23 0.70 4 Cycle 0.96 0.96 0.54 0.53 0.78 5Cycle 0.94 0.90 0.52 0.51 0.56 Appearance (visual) 1 Cycle sedimentationsedimentation clear supernatant, sedimentation opaque two layers twolayers a thin opaque two layers supernatant flocculation layer withbetween, clear floccules supernatant and sedimentation, sedimentationtwo layers 2 Cycle sedimentation sedimentation clear supernatantsedimentation opaque two layers two layers two layers, supernatant milkywith supernatant floccules with flocculus 3 Cycle sedimentationsedimentation clear supernatant An opaque opaque two layers two layerssupernatant supernatant on top, with a thick milky flocculesflocculation layer between opaque supernatant and sedimentation,sedimentation two layers 4 Cycle sedimentation sedimentation two clearsupernatant clear supernatant opaque two layers layers sedimentationsupernatant two layers with floccules 5 Cycle sedimentation clear toopaque clear supernatant clear supernatant A thin clear two layerssupernatant, sedimentation supernatant on sedimentation two top, a thicktwo layers layers opaque flocculation layer between clear supernatantand sedimentation Redispersibility 1 Cycle redispersible redispersibleredispersible; redispersible redispersible sedimentation occurs at 10min after shaking 2 Cycle redispersible redispersible redispersible:redispersible redispersible sedimentation occurs at 10 min after shaking3 Cycle redispersible redispersible redispersible; redispersibleredispersible sedimentation occurs at 10 min after shaking 4 Cycleredispersible redispersible redispersible; redispersible; redispersiblesedimentation sedimentation occurs occurs at 30 min at 10 min aftershaking after shaking, sedimentation appears loose and curdy 5 Cycleredispersible redispersible redispersible; redispersible; redispersiblesedimentation sedimentation occurs at 10 min occurs at 10 min aftershaking, after shaking sedimentation appears loose and curdy pH 1 Cycle5.70 5.77 5.71 5.70 5.63 2 Cycle 5.67 5.68 5.67 5.73 5.61 3 Cycle 5.615.58 5.70 5.65 5.53 4 Cycle 5.57 5.58 5.62 5.64 5.55 5 Cycle 5.62 5.585.57 5.62 5.47 Particle 1 Cycle 4.10 ± 2.63 4.09 ± 3.04 3.96 ± 2.41 4.09± 3.14 4.08 ± 2.76 size (μm) 2 Cycle 4.31 ± 3.66 4.37 ± 3.29 4.13 ± 2.774.22 ± 2.45 4.16 ± 2.58 3 Cycle 4.36 ± 3.43 4.37 ± 3.01 4.36 ± 3.20 4.41± 3.42 4.41 ± 3.11 4 Cycle 4.44 ± 3.31 4.38 ± 3.19 4.47 ± 3.05 4.48 ±3.23 4.46 ± 3.00 5 Cycle 4.47 ± 2.87 4.49 ± 2.98 4.47 ± 3.28 4.50 ± 3.064.48 ± 2.92

It was observed that suspensions with 3% Methocel F50 or 3% Methocel E50as suspending agents showed good stability for 14 days and after 5freeze-thawing cycles, but slow reconstitution rates were observed whendispersing blends in purified water.

Suspensions using 0.5% Methocel A4MP as suspending agent showed looseand curdy sedimentation during stability study, indicatingincompatibility.

However, 0.5% Methylcellulose (400 cps) or 3% Klucel JF Pharm assuspending agents showed good reconstitution rate and acceptablestability and therefore could be used as alternative suspending agentsfor the target formulation.

Example 6: Optimization of Suspending Anent Concentration forDispersibility Study (Using Simethicone Granular MED-342)

According to the observations of DS-54 to DS-58, concentrations ofMethocel F50, Methocel E50, and Klucel JF Pharm were decreased forbetter dispersibility, while concentration of Methylcellulose 400 cpswas increased for a balance between dispersibility and viscosity.Simethicone in the formulations was changed to the granular solid form(MED-342), which simplifies the process by avoiding adsorbing liquidsimethicone on lactose. The compositions are shown in Table 12.

TABLE 12 Composition of blends using Simethicone granular solid Quantityper unit (mg) S.# Ingredients DS-54 DS-55 DS-57 DS-58 DS-63 DS-64 DS-65DS-66 DS-67 DS-68 DS-69 DS-70 1 Tecovirimat Granules 346.50 346.50346.50 346.50 346.50 346.50 346.50 346.50 346.50 346.50 346.50 346.50 2Sucralose, NF 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.0010.00 10.00 10.00 3 Simethicone 10.00 10.00 10.00 10.00 10.00 10.0010.00 10.00 10.00 10.00 10.00 10.00 granular solid, USP (MED-342) 4Lactose Monohydrate, 483.50 483.50 608.50 483.50 508.50 508.50 583.50508.50 533.50 533.50 558.50 533.50 NF (SuperTab 11SD) 5 Hypromellose150.00 — — — 125.00 — — — 100.00 — — — (Methocel F 50) Hypromellose150.00 — — — 125.00 — — — 100.00 — — (Methocel E 50) Methyl Cellulose, —— 25.00 — — — 50.00 — — — 75.00 — 400 cps, USP Hydroxypropyl — — —150.00 — — — 125.00 — — — 100.00 cellulose (Klucel JF Pharm), NF 6Purified water, — — — — — — — — — — — — USP, Q.S. to 5 mL Total 1000.001000.00 1000.00 1000.00 1000.00 1000.00 1000.00 1000.00 1000.00 1000.001000.00 1000.00

In general, the formulation procedures include:

-   -   1. blending of Tecovirimat granules and simethicone granular        solid (MED-342), then passing through Quadro Comil equipped with        2B039R03125173*(991) screen;    -   2. weighing of quantity equivalent to 40 g of        Simethicone-Tecovirimat granules blend and mixing geometrically        with other components;    -   3. passing again of the blend through Quadro Comil using        2B039R03125173*(991) screen and    -   4. dispersing of 1 dose in purified water to make Q.S. to 5 mL,        followed by evaluation of dispersibility and dissolution (Table        13).

TABLE 13 Observation of reconstitution and dissolution Formulation IDS.# Properties DS-54 DS-55 DS-57 DS-58 1 Chunks Big Big None Veryremaining chunks chunks small at bottom chunks after shaking DissolutionTime % SD % SD % SD % SD 2 (n = 3) (mins) Released Released ReleasedReleased 5 78.5 4.5 85.3 2.3 83.6 2.6 72.7 1.5 10 76.6 5.7 83.7 1.9 82.41.9 81.8 1.5 15 76.0 6.7 84.2 1.6 82.5 1.1 83.2 1.6 30 76.1 6.3 84.2 2.084.0 0.2 85.8 0.8 45 76.1 6.2 84.0 2.0 83.7 1.1 86.7 2.3 Formulation IDS.# Properties DS-63 DS-64 DS-65 DS-66 DS-67 DS-68 DS-69 DS-70 1 Chunksremaining at Mediun Medium Small None Small Small Small None bottomafter shaking chunks chunks chunks chunks chunks chunks

The % ST-246 is shown in FIG. 1 .

It was observed that when concentrations of Methocel F50 and MethocelE50 decreased to 2.0% w/v (DS-67 and DS-68), there were still chunksremaining after shaking manually. Hydration rates of these two polymersare fast such that the gel layers developed inhibit the wetting ofinside materials, leading to fish eyes and bad dispersibility.Concentration of 0.5-1.0% w/v Methylcellulose 400 cps and 2.0-2.5% w/vKlucel JF Pharm can reach a balance between good dispersibility andviscosity.

Example 7: Evaluation of a Combination of Suspending Agents

Combinations of suspending agents were used for dissolution study.Compositions arc given in Table 14. The Target formulation using AvicelCL-611 as a suspending agent exhibits floating in the form of lumps indissolution test.

TABLE 14 Composition of solid blends using combination of suspendingagents Quantity per unit (ng) Prototype 1 Prototype 2 Prototype 3Prototype 4 S.# Ingredients (DS-59) (DS-60) (DS-61) (DS-62) 1Tecovirimat Granules 346.50 346.50 346.50 346.50 2 Simethicone granular10.00 10.00 10.00 10.00 solid, USP (MED-342) 3 Lactose Monohydrate, NF328.50 348.50 373.50 370.50 (SuperTab 11SD) 4 Avicel CL-611, NF 50.0025.00 5 Methyl Cellulose, 400 cps, 15.00 20.00 15.00 20.00 USP 6Xantural 75 — — 5.00 3.00 7 Purified water, USP, — — — — Q.S. to 5 mLTotal 750.00 750.00 750.00 750.00

The formulation procedures was as follows;

-   -   1. blending of Tecovirimat granules and Simethicone granular        solid (MED-342), then passing through Quadro Comil equipped with        213039R03125173*(991) screen;    -   2. weighing of the quantity equivalent to 30 units of        Simethicone-Tecovirimat blend and then geometric mixing with        other components; shaking and mixing of blend in a zip-lock bag;    -   3. dispersing of 1 dose in purified water to make Q.S. to 5 mL        for dissolution test (Table 15).

TABLE 15 Dissolution of suspensions using combination of suspendingagents Formulation ID Prototype 1 Prototype 2 Prototype 3 Prototype 4S.# Properties (DS-59) (DS-60) (DS-61) (DS-62) 1 Dispersibility Smallchunks Small chunks Small chunks Small chunks remaining after remainingafter remaining after remaining after shaking shaking shaking shaking 2Viscosity Good viscosity Watery Watery Watery 3 Dissolution Instantdispersion Instant dispersion Gel clumps Gel clumps with formation ofwith formation of coarse particulates line particulates

Example 8: Optimizing Anti-Foaming Agent and Viscosity

The suspensions were optimized for defoaming and viscosity of suspensionby changing the level of simethicone solid granular and methylcellulose400 cps in reference formulation DS-60. The methylcellulose 400 cps wasreplaced with Klucel JF Pharm and formulated to test the effect onfoaminess. The compositions are given in Table 16.

TABLE 16 Composition of DS-60A to DS-60E and DS-71 Quantity per unit(mg) S.# Ingredients DS-60A DS-60B DS-60C DS-60D DS-60E DS-71 1Tecovirimat Granules 346.50 346.50 346.50 346.50 346.50 346.50 2Simethicone granular 16.67 25.00 16.67 16.67 16.67 16.67 solid, USP(MED-342) 3 Lactose Monohydrate, 341.83 333.50 336.83 331.83 331.83341.83 NF (SuperTab 11SD) 4 Avicel CL-611, NF 25.00 25.00 25.00 25.0025.00 25.00 Methyl Cellulose. 20.00 20.00 25.00 30.00 37.50 — 400 cps,USP Hydroxypropyl cellulose — — — — — 20.00 (Klucel JF Pharm), NF 5Purified water, — — — — — — USP, Q.S. to 5 mL Total 750.00 750.00 750.00750.00 757.50 750.00

The formulation procedures included

-   -   1. geometric mixing of quantity equivalent to 30 units of        lactose monohydrate and simethicone (MED-342), then geometric        mixing with other components;    -   2. passing of the blend through Quadro Comil equipped with        2B039R03125173*(991) screen and    -   3. dispersing of 1 dose in purified water to make Q.S. to 5 mL        to test foaminess and viscosity (Table 17).

TABLE 17 Observation of foaminess and viscosity of DS-60A to DS-60E andDS-71 Formulation ID S.# Properties DS-60A DS-60B DS-60C DS-60D DS-60EDS-71 1 Dispersibility Easy to Easy to Easy to Easy to Small chunks Easyto disperse, disperse, disperse, disperse, remaining disperse, no chunksno chunks no chunks no chunks after no chunks remaining remainingremaining remaining shaking remaining 2 Foaminess Less foam DecreasedDecreased Decreased Decreased Less foam than foam foam foam foam thanDS-60 DS-60A 3 Viscosity Watery Watery Watety Watery Good Wateryviscosity

It was observed that the level of 16.67-25 mg per unit of Simethicone(MED-342) attains a good anti-foaming effect. The replacement of KlucelF Pharm with Methylcellulose 400 cps also decreases foaminess. Goodviscosity in suspension was observed when Methylcellulose 400 cps levelreached 0.75% w/v.

Example 9: Methylcellulose (400 cps and 15 cps) Combination asSuspending Agents

The level of Methylcellulose 15 cps was adjusted for betterdispersibility. Compositions are given in Table 18.

TABLE 18 Composition of DS-72 to DS-74 Quantity per unit (mg) S.#Ingredients DS-72 DS-73 DS-74 1 Tecovirimat Granules 346.50 346.50346.50 2 Simethicone granular solid, USP 16.67 16.67 16.67 (MED-342) 3Lactose Monohydrate, NF 349.33 349.33 349.33 (SuperTab 11SD) 4 MethylCellulose, 400 cps, USP 37.50 33.50 30.00 Methyl Cellulose, 15 cps, USP— 4.00 7.50 5 Purified water, USP, — — — Q.S. to 5 mL Total 750.00750.00 750.00

The formulation procedure included

-   -   1. geometric mixing of Tecovirimat granules, lactose monohydrate        and Simethicone (MED-342) and passing of blend through Quadro        Comil equipped with 2B039R03125173*(991) screen;    -   2. weighing of quantity equivalent to 10 units of blend and then        geometric mixing with polymer(s) and    -   3. dispersing of 1 dose in purified water to make Q.S. to 5 ml,        to test dispersibility.    -   It was observed that all three formulations were easy to        disperse with no chunks remaining after shaking. With decreased        level of Methylcellulose 400 cps in formulation, suspension was        more watery, suggesting it's better to keep Methylcellulose 400        cps more than 0.75% w/v.

Example 10: Optimizing levels of Methylcellulose 15 cps and Simethiconein Methylcellulose Combination for Rapid Hydration

Methylcellulose 400 cps concentration was kept as 1.0% w/v, and theamount of Methylcellulose 15 cps was adjusted for betterdispersibility/hydration and the level of Simethicone (MED-342) adjustedto investigate the anti-foaming effect. Compositions are given in Table19. Total blends were decreased to 500 mg per unit.

TABLE 19 Composition of DS-75 to DS-82 Quantity per unit (mg) S.#Ingredients DS-75 DS-76 DS-77 DS-78 DS-79 DS-80 DS-81 DS-82 1Tecovirimat Granules 346.50 346.50 346.50 346.50 346.50 346.50 346.50346.50 2 Sucralose, NF 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 3Simethicone granular 20.00 20.00 20.00 20.00 20.00 25.00 30.00 35.00solid, USP (MED-342) 4 Lactose Monohydrate, 43.50 63.50 53.50 43.5058.50 53.50 53.50 53.50 NF (SuperTab 11SD) 5 Methyl Cellulose, 50.0050.00 50.00 50.00 50.00 50.00 50.00 50.00 400 cps, USP Methyl Cellulose,— 5.00 15.00 25.00 10.00 15.00 15.00 15.00 15 cps, USP 6 Strawberryflavor, 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 #133.16296 7 Purifiedwater, — — — — — — — — USP, Q.S. to 5 mL Total 475.00 500.00 500.00500.00 500.00 505.00 510.00 515.00

The formulation procedure was as follows;

-   -   1. geometric mixing of quantity equivalent to 100 units of        Tecovirimat granules, sucralose, lactose monohydrate,        Simethicone (MED-342) and Methylcellulose 400 cps in DS-75, then        passing of blend through Quadro Comil equipped with        2B039R03125173*(991) screen;    -   2. for DS-75, weigh quantity equivalent to 50 units of blend and        then geometric mixing with strawberry flavor;    -   3. for DS-77, weigh quantity equivalent to 30 units of blend and        then geometric mixing with strawberry flavor, Methylcellulose 15        cps, and lactose monohydrate;    -   4. for DS-76 to DS-79, weigh quantity equivalent to 10 units of        DS-75 and then geometric mixing with other components.    -   5. for DS-80 to DS-82, weigh quantity equivalent to 5 units of        DS-77 and then geometric mixing with other components and    -   6. dispersing of 1 dose in purified water to make Q.S. to 5 mL        to test dispersibility, foaminess and sedimentation (Table 20).

TABLE 20 Observation of suspensions of DS-75 to DS-82 Formulation ID S.#Properties DS-75 DS-76 DS-77 DS-78 DS-79 DS-80 DS-81 DS-82 1Dispersibility small very no no no big big big (chunks remaining atchunks tiny chunks chunks chunks chunks chunks chunks bottom aftershaking) chunk 2 Settlement/ T = 0 No sedimentation. Foam is similar inall formulations foaminess T = 30 min No sedimentation. Individualbubbles are smaller in DS-80, DS-81, DS-82 T = 1 hr No sedimentation.Individual bubbles are smaller in DS-80, DS-81, DS-82 Quantity of foamis less inDS-80, DS-81, DS-82 T = 2 hr No sedimentation. A very thinlayer of foam in DS-80 and DS-81. No foam in DS-82. T = 17 hr FoaminessNo foam in all formulations Sedimentation 0.82 0.84 0.86 0.86 0.86 0.860.82 0.82 coefficient Second 4 4 4 4 4 4 5 5 layer (mm)

It was observed that methylcellulose 15 cps level of 10-25 mg perTecovirimat dosage unit can lead to good dispersibility/hydration. Therewas no significant difference in foaminess of suspensions initially andafter 17 hours of reconstitution in formations with Simethicone level of20-35 mg per unit. The big chunks in formulation with 25-35 mgSimethicone per unit may be caused by Simethicone agglomeration,suggesting that it is advantageous to keep Simethicone as 20 mg perunit. All formulations showed good viscosity with 1% w/v Methylcellulose400 cps.

Example 11: Scale-Up of the Optimized Compositions

Scale-up batches using methylcellulose (400 cps) and Klucel JXF Pharm assuspending agents were prepared and evaluated. Compositions are given inTable 21.

TABLE 21 Composition of Scale-Up batches Quantity per unit (mg) Goal:Using Methylcellulose (400 cps and 15 cps) as a suspending Goal: UsingHydroxypropyl Cellulose agent (Klucel JXF Pharm) as a suspending (500 gscale). agent (500 g scale). Batch: FSIG- Batch: FSIG- Batch: FSIG-Batch: FSIG- 20140826-1 20140826-2 20141216-1 20141216-2 S. #Ingredients (DS-75) (DS-77) (DS-83) (DS-84) 1 Tecovirimat 346.49 346.49346.50 346.50 Granulate 2 Lactose 66.01 51.01 93.00 — monohydrate, NF(SuperTab 11SD) 3 Methylcellulose, 50.00 50.00 — — 400 cps, USP 4Methylcellulose, — 15.00 — — 15 cps, USP 5 Hydroxylpropyl — — 125.00118.00 Cellulose (Klucel JXF Pham) 6 Sucralose, NF 10.00 10.00 10.0010.00 7 Strawberry flavor, 5.00 5.00 — — #133.16296 8 Black cherry Nat —— 3.00 3.00 type flavor 9 Simethicone 20.00 20.00 20.00 20.00 GranularSolid (MED-342), USP 10 Magnesium 2.50 2.50 2.50 2.50 stearate, NF Totalweight (mg) 500.00 500.00 600.00 500.00

The batch size of each composition was 0.500 kg. In general, theformulation procedure involved the following steps:

-   -   1. Sieving of the Tecovirimat granules and granular Simethicone        through Quadro Comil equipped with 2B039R03125173*(991) screen.    -   2. Sieving of the Tecovirimat granulate and granular Simethicone        through a #20 screen.    -   3. Sieving of lactose through a #20 screen, then addition of        Flavor on lactose with geometric mixing using spatula.    -   4. Sieving of polymer and sucralose through a #40 screen.    -   5. Blending of the Tecovirimat-Simethicone blend and other        extra-granular components in the V-blender for 15 minutes.    -   6. Passing of magnesium stearate through a #40 screen, then        addition as a lubricant to above milled blend and lubricate for        5 minutes.    -   7. Evaluation of the physicochemical properties of blend (Table        22).    -   8. Transfer of 10 doses of blend to a 100 cc glass bottle. Add        water Q.S. to 50 mL. Shake well to mix the content. Evaluate the        physicochemical properties of suspension (Table 21).    -   9. Packing of 20 doses of blend in Stick pack PAKVF2.5M Fin seal        pouches (part #25M0275FS06) Size 2.5 inch×6 inch. Heat-seal        properly. Prepare 15-20 pouches for stability/dissolution study        (Table 24).

TABLE 22 Physicochemical properties of blends of scale-up batches Batch:FSIG- Batch: FSIG- Batch: FSIG- Batch: FSIG- S# Property 20140826-120140826-2 20141216-1 20141216-2 1 Appearance White powder White powderWhite powder White powder 2 Flow of Lubricated Blend 24 26 26 28 (FlodexOrifice mm) 3 Bulk Density (g/cc) 0.541 0.520 0.505 0.468 Tap Density(g/cc) 0.693 0.667 0.640 0.607 Compressibility Index (%) 21.9 22.0 21.122.9 4 Granules Retained on Sieve 0.01 0.01 0.02 0.02 # 20 (opening size0.850 mm) (%) Granules Retained on Sieve 1.85 2.22 3.29 3.52 # 30(opening size 0.600 mm) (%) Granules Retained on Sieve 9.37 10.46 8.6010.61 # 40 (opening size 0.425 mm) (%) Granules Retained on Sieve 8.649.72 10.72 12.48 # 50 (opening size 0.300 mm) (%) Granules Retained onSieve 4.12 4.36 4.06 5.24 # 60 (opening size 0.250 mm) (%) GranulesRetained on Sieve 10.53 11.84 12.33 12.29 # 80 (opening size 0.180 mm)(%) Retained on Pan (size 65.47 61.40 60.96 55.84 <0.180 mm) (%) MeanSize (mm) 0.106 0.119 0.121 0.139

TABLE 23 Physicochemical properties of suspensions of scale-up batchesS# Property Batch: FSIG-20140826-1 Batch: FSIG-20140826-2 1Reconstitution After manual shaking, After manual shaking, fish fisheyes were observed eye was observed at at 4 positions at only oneposition at bottom of bottle. bottom of bottle. 2 Appearance Whitedispersion White dispersion after reconstitution 3 pH of 5.98 6.00suspension 4 Microscopic Particle size 3.16 ± 2.37 μm. Particle size3.20 ± 2.63 μm. observation No agglomeration observed. No agglomerationobserved. 5 Physical No phase separation or No phase separation orstability agglomeration. agglomeration. 6 Forced RedispersibleRedispersible settling and redispersibility 7 Observation of 10 min 30min 24 hr 10 min 30 min 24 hr sedimentation At 25° C. Sedimentation 1.001.00 1.00 1.00 1 00 1.00 coefficient Separation None None Second NoneNone Second layer layer (29% (29% height) height) RedispersibilityRedispersible Redispersible Redispersible Redispersible RedispersibleRedispersible At 5° C. Sedimentation 1.00 1.00 1.00 1.00 100 1.00coefficient Separation None None Second None None Second layer layer(23% (20% height) height) Redispersibility Redispersible RedispersibleRedispersible Redispersible Redispersible Redispersible S# PropertyBatch: FSIG-20141216-1 Batch: FSIG-20141216-2 1 Reconstitution Aftermanual shaking, After manual shaking, fish eyes were observed no fisheye was at 2 positions at observed, disperse bottom of bottle. verywell. 2 Appearance White dispersion White dispersion afterreconstitution 3 pH of 5.99 6.15 suspension 4 Microscopic Particle size3.04 ± 2.11 μm. Particle size 3.13 ± 2.53 μm. observation Noagglomeration observed. No agglomeration observed. 5 Physical No phaseseparation. Small No phase separation. Small stability agglomerationsare observed agglomerations are observed when pouring out. when pouringout. 6 Forced Redispersible Redispersible settling and redispersibility7 Observation of 10 min 30 min 24 hr 10 min 30 min 24 hr sedimentationAt 25° C. Sedimentation 1.00 1.00 0.56 1.00 1.00 0.58 coefficientSeparation None None None None None None Redispersibility RedispersibleRedispersible Redispersible Redispersible Redispersible Redispersible At5° C. Sedimentation 1.00 1.00 0.89 1.00 1.00 0.88 coefficient SeparationNone None None None None None Redispersibility RedispersibleRedispersible Redispersible Redispersible Redispersble Redispersible

TABLE 24 Stability and dissolution of scale-up batches Batch: FSIG-Batch: FSIG- Batch: FSIG- Batch: FSIG- 20140820-1 20140826-2 201412145-120141216-2 Property (DS75) (DS77) (DS83) (DS84) Time % % % % S# (mins)Released SD Released SD Released SD Released SD 1 Dissolution 5 88.6 1.388.4 1.5 84.2 6.7 92.4 4.2 (n = 6) 10 90.2 1.7 92.3 1.5 93.9 4.4 97.61.7 55 89.4 1.5 90.5 2.8 94.1 2.0 99.3 1.7 30 90.4 1.3 90.2 1.4 96.9 0.9101.4 2.2 45 93.6 2.5 90.7 1.5 97.1 1.0 100.3 0.7

The % ST-246 released is shown in FIG. 2 .

Example 12: Effect of Particle Sizes of API on Formulation Properties

To study the effect of particle sizes of API on formulation performanceproperties, such as dissolution, use API of different particle sizes forgranulation process. Compositions are given in Table 25.

TABLE 25 Composition of DS-85 to DS-87 using API of different particlesizes Quantity per unit (mg) Goal: Using API of different particle sizesfor granulation process (288.6 g scale). Ref. DS- 77 (Batch #FSIG-20140826-2) Batch: FSIG-20150120-1 Batch: FSIG-20150120-2 Batch:FSIG-20150120-3 S. # Ingredients (DS-85) (DS-86) (DS-87) IntragranularIngredients: 1 Tecovirimat monohydrate, 209.0 209.0 209.0 micronizedusing API Lot# SG-10C12- using API Lot# SG-10C12- using API Lot#SG-10C12- T1039 (Trial #2, d90-21.51 T1039 (Trial #3, d90-38.74 T1039(Trial #4, d90-81.53 μm) μm) μm) 2 Colloidal silicon dioxide, NF 1.951.95 1.95 (Cabosil M5P) 3 Croscarmellose sodium, NF 31.32 31.32 31.32(AcDiSol) 4 Lactose monohydrate, NF 33.15 33.15 33.15 (SuperTab 11SD) 5Microcrystalline cellulose. NF 49.62 49.62 49.62 (Avicel PH 101)Intragranular Ingredients Total 325.04 325.04 325.04 Granulating Fluid:6 Hypromellose, USP (Methocel E3 13.65 13.65 13.65 LV Prem.) 7 Sodiumlauryl sulfate, NF 7.80 7.80 7.80 8 Purified water, USP* 170.1 170.1170.1 Granulating Fluid Solids Total 21.45 21.45 21.45 Granulate Solids346.49 346.49 346.49 Extragranular Ingredients: 9 Lactose monohydrate,NF 51.01 51.01 51.01 (SuperTab 11SD) 10 Methylcellulose, 50.0 50.0 50.0400 cps, USP 11 Methylcellulose, 15.0 15.0 15.0 15 cps, USP 12Sucralose, NF 10.0 10.0 10.0 13 Strawberry flavor, #133.16296 5.0 5.05.0 14 Simethicone Granular Solid 20.0 20.0 20.0 (MED-342), USP 15Magnesium stearate, NF 2.5 2.5 2.5 Powder for Reconstitution Blend Total500.00 500.00 500.00 *Removed during the drying process.

The batch size of each composition was 0.2886 Kg. Detailed experimentalprocedures and results of each trial formulation were recorded in theexecuted batch records. In general, the formulation procedure involvedthe following steps:

-   -   1. Passing of intragranular components through a #20 screen.    -   2. Mixing of intragranular components containing diluents,        disintegrant, in GMX-High Shear Granulator/Mixer (1 L bowl) at        impeller blade speed 460 rpm and chopper speed of 2000 rpm for 2        minutes.    -   3. Addition of granulating solution containing surfactant,        binder (7.1% w/w Hypromellose Methocel E3 solution) and mixing        with the intragranular components in GMX-High Shear        Granulator/Mixer at impeller blade speed 460 rpm and chopper        blade 2000 rpm for 8-10 minutes.    -   4. Addition of about 1.5 g water to rinse the container,        granulation for additional 2 minutes, recording of the visual        observation of the wet mixture.    -   5. Drying of wet granular mass using a Midi-Glatt fluid bed        dryer/processor at inlet temperature 35-40° C. until the loss on        drying (LOD) of the granules reached the range of 4.00-5.50%        w/w, following are the typical drying parameters.

Parameters Units Product Air Pressure (bar) 0.25-0.30 Inlet AirTemperature (° C.) 35 Filter Blowing Rate (Sec)  1 Product Temperature(° C.)-at end   20-21

-   -   6. Passing of the dried granules through Quadro Comil equipped        with 2R039R03125173*(991) screen.    -   7. Weighing of the granules, then recalculation and weighing of        extragranular ingredients.    -   8. Passing of the Tecovirimat granules and granular Simethicone        through Quadro Comil equipped with 2B039R03125173*(991) screen.    -   9. Passing of the Tecovirimat granulate and granular Simethicone        through a #20 screen.    -   10. Passing of lactose through a #20 screen and addition of        Flavor on lactose with geometric mixing using spatula.    -   11. Passing of polymer and sucralose through a #40 screen.    -   12. Blending of the Tecovirimat-Simethicone blend and other        extragranular components in the V-blender for 15 minutes.    -   13. Passing of magnesium stearate through a #40 screen, then        addition as a lubricant to above milled blend and lubricate for        5 minutes.    -   14. Evaluation of the physicochemical properties of blend (Table        26).    -   15. Transfer of 10 doses of blend to a 100 cc glass bottle. Add        water Q.S. to 50 mL. Shake well to mix the content. Evaluate the        physicochemical properties of suspension (Table 27).    -   16. Packing of 20 doses of blend in Stick pack PAKVF2.5M Fin        seal pouches (part #25M0275FS06); size 2.5 inch×6 inch.        Heat-seal properly. Prepare 3 pouches for dissolution study        (Table 28).

TABLE 26 Characterization of blends DS-85 to DS-87 Batch: FSIG- Batch:Batch: FSIG- 20150120-1 FSIG-20150120-2 20150120-3 S# Property (DS-85)(DS-86) (DS-87) 1 Appearance White powder White powder White powder 2Flow of Lubricated Blend 24 24 24 (Flodex Orifice mm) 3 Bulk Density(g/cc) 0.454 0.436 0.426 Tap Density (g/cc) 0.605 0.590 0.568Compressibility Index (%) 25.0 26.1 25.0 4 Granules Retained on Sieve #20 0.02 0.02 0.02 (opening size 0.850 mm) (%) Granules Retained on Sieve# 30 8.03 4.84 2.04 (opening size 0.600 mm) (%) Granules Retained onSieve # 40 18.50 18.50 8.81 (opening size 0.425 mm) (%) GranulesRetained on Sieve # 50 14.86 12.11 10.99 (opening size 0.300 mm) (%)Granules Retained on Sieve # 60 5.32 3.60 6.14 (opening size 0.250 mm)(%) Granules Retained on Sieve # 80 37.04 28.28 38.65 (opening size0.180 mm) (%) Retained on Pan (size <0.180 16.24 32.65 33.35 mm) (%)Mean Size (mm) 0.252 0.204 0.168

TABLE 27 Characterization of suspensions of DS-85 to DS-87 Batch:FSIG-20150120-1 Batch: FSIG-20150120-2 S# Property (DS-85) (DS-86) 1Reconstitution After manual shaking, no fish eyes is After manualshaking, no fish eye is observed, disperse very well. observed, dispersevery well. 2 Appearance after White dispersion White dispersionreconstitution 3 pH of suspension 6.11 6.10 4 Microscopic Particle size4.10 ± 3.42 μm. No Particle size 4.40 ± 3.52 μm. No observationagglomeration observed. agglomeration observed. 5 Physical stability Nophase separation or agglomeration. No phase separation or agglomeration.6 Forced settling and Redispersible Redispersible redispersibility 7Observation of 10 min 30 min 24 hr 10 min sedimentation At 25° C.Sedimentation 1.00 1.00 1.00 1.00 coefficient Separation None NoneSecond layer None (22% height) Redispersibility RedispersibleRedispersible Redispersible Redispersible At 5° C. Sedimentation 1.001.00 1.00 1.00 coefficient Separation None None Second layer None (22%height) Redispersibility Redispersible Redispersible RedispersibleRedispersible Batch: FSIG-20150120-2 Batch: FSIG-20150120-3 S# (DS-86)(DS-87) 1 After manual shaking, no fish eye is After manual shaking, nofish eye is observed, disperse very well. observed, disperse very well.2 White dispersion White dispersion 3 6.10 6.12 4 Particle size 4.40 ±3.52 μm. No Particle size 4.84 ± 4.22 μm. No agglomeration observed.agglomeration observed. 5 No phase separation or agglomeration. No phaseseparation or agglomeration. 6 Redispersible Redispersible 7 30 min 24hr 10 min 30 min 24 hr At 25° C. 1.00 1.00 1.00 1.00 1.00 None Secondlayer None None Second layer (22% height) (26% height) RedispersibleRedispersible Redispersible Redispersible Redispersible At 5° C. 1.001.00 1.00 1.00 1.00 None Second layer None None Second layer (25%height) (25% height) Redispersible Redispersible RedispersibleRedispersible Redispersible

TABLE 28 Dissolution profile of DS-85 to DS-87 Property Batch:FSIG-20150120-1 Batch: FSIG-20150120-2 Batch: FSIG-20150120-3 Time(DS-85) (DS-86) (DS-87) S# (mins) % Released SD % Released SD % ReleasedSD 1 Dissolution 5 72.5 1.6 58.8 1.5 36.0 1.2 (n = 6) 10 82.2 0.7 66.73.0 46.0 0.9 15 85.5 1.1 71.8 2.3 51.7 0.8 30 88.2 2.3 75.7 3.3 60.2 1.745 90.3 2.0 80.4 3.0 64.7 1.0

It was observed that DS-85 (API D90=21.51 μm) showed higher dissolutionrate compared to DS-86 (API D90=38.74 μm) and DS-87 (API D90=81.53 μm).The particle size of the Tecovirimat monohydrate used for granulation isinversely proportional to the dissolution rate. Smaller particle APIbatches showed higher dissolution rate as; DS-85>DS-86>DS-87 (see FIG. 3).

Example 13: Optimization of Blending and Lubrication Time TecovirimatMonohydrate Powder for Reconstitution

To study the effect of blend/lubrication time on blend uniformity anddissolution, sample where taken at different time points during ablending range of 10-25 minutes and a lubrication of 3-10 minutes.Composition is given in Table 29.

TABLE 29 Composition of DS-88 Quantity per unit (mg) Goal: Blend or lubetime DOE study (500 g scale). Ref. DS-75 (Batch # FSIG-20140826-1)Batch: FSIG-20150317-1 S. # Ingredients (DS-88) 1 Tecovirimat Granulate346.49 2 Lactose monohydrate, NF 66.01 (SuperTab 11SD) 3Methylcellulose, 400 cps, 50.00 USP 4 Sucralose, NF 10.00 5 Strawberryflavor, 5.00 #133.16296 6 Simethicone Granular Solid 20.00 (MED-342),USP 7 Magnesium stearate, NF 2.50 Total weight (mg) 500.00

The batch size was 0.500 Kg. In general, the formulation procedureinvolved the following steps:

-   -   1. Passing of the Tecovirimat granules and granular Simethicone        through Quadro Comil equipped with 2B039R03125173*(991) screen;    -   2. Passing of the Tecovirimat granulate and granular Simethicone        through a #20 screen;    -   3. Passing of lactose through a #20 screen, then addition of        Flavor on lactose with geometric mixing using spatula;    -   4. Passing of polymer and sucralose through a #40 screen;    -   5. Blending of the Tecovirimat-Simethicone blend and other        extragranular components in the V-blender, taking a 10 g sample        at 10, 15, and 20 minutes. Halt the process at 25 minutes and        repeat sampling;    -   6. Passing of magnesium stearate through a #40 screen, then        addition of 2.3 g as a lubricant to the remaining blend for        lubrication. Take a 10 g sample at 3, 5, and 7.5 minutes. Final        lubrication time is 10 minutes and repeat sampling;    -   7. Evaluation of the physicochemical properties of blend (Table        30);    -   8. Transfer of 10 doses of blend to a 100 cc glass bottle. Add        water Q.S. to 50 mL. Shake well to mix the content. Evaluate the        physicochemical properties of suspension (Table 31);    -   9. Addition of Q.S. purified water to 10 g samples at different        blending or lube time points to make 100 mL, then stirring well        for tests of reconstitution and dissolution (Table 32A and 32        B).

TABLE 30 Characterization of Blend DS-88 Batch: FSIG- 20150317-1 S#Property (DS-88) 1 Appearance White powder 2 Flow of Lubricated Blend(Flodex 24 Orifice mm) 3 Bulk Density (g/cc) 0.518 Tap Density (g/cc)0.700 Compressibility Index (%) 26.0 4 Granules Retained on Sieve # 200.01 (opening size 0.850 mm) (%) Granules Retained on Sieve # 30 4.09(opening size 0.600 mm) (%) Granules Retained on Sieve # 40 10.36(opening size 0.425 mm) (%) Granules Retained on Sieve # 50 9.20(opening size 0.300 mm) (%) Granules Retained on Sieve # 60 4.03(opening size 0.250 mm) (%) Granules Retained on Sieve # 80 14.76(opening size 0.180 mm) (%) Retained on Pan (size <0.180 mm) 57.55 (%)Mean Size (mm) 0.133

TABLE 31 Characterization of suspension of DS-88 Batch: FSIG-20150317-1S# Property (DS-88) 1 Reconstitution After manual shaking, 1 fish eye isobserved at bottom of bottle. 2 Appearance after White dispersionreconstitution 3 pH of suspension 6.13 4 Microscopic observationParticle size 3.28 + 2.72 μm. No agglomeration observed. 5 Physicalstability No phase separation or agglomeration. 6 Forced settling andRedispersible redispersibility 7 Observation of sedimentation 10 min 30min 24 hr At 25° C. Sedimentation coefficient 1.00 1.00 1.00 SeparationNone None Second layer (22% height) Redispersibility RedispersibleRedispersible Redispersible At 5° C. Sedimentation coefficient 1.00 1.001.00 Separation None None Second layer (20% height) RedispersibilityRedispersible Redispersible Redispersible

TABLE 32A Reconstitution and Dissolution of Samples at DifferentBlending Times (see FIG. 4) Batch: FSIG-20150317-1 (DS-88) BlendingBlending Blending Blending 10 minutes 15 minutes 20 minutes 25 minutesS# Property (no lubricant) (no lubricant) (no lubricant) (no lubricant)1 Reconstitution Tiny lumps, a little foam Tiny lumps, a little foamTiny lumps, a little foam Tiny lumps, a little foam Time % % % % (mins)Released SD Released SD Released SD Released SD 2 Dissolution 5 90.6 1.092.5 2.4 90.2 1.1 92.3 1.2 (n = 6) 10 92.8 1.7 93.6 0.5 91.8 1.7 93.31.4 15 94.7 0.7 93.7 1.4 91.8 1.0 94.0 1.0 30 94.2 0.9 92.6 1.9 91.5 1.893.2 1.0 45 94.8 0.7 93.6 1.9 91.9 1.1 93.2 0.8

TABLE 32B Reconstitution and Dissolution of Samples at DifferentLubrication Time (see FIG. 5) Batch: FSIG-20150317-1 (DS-88) LubricationLubrication Lubrication Lubrication 3 minutes 5 minutes 7.5 minutes 10minutes S# Property (with lubricant) (with lubricant) (with lubricant)(with lubricant) 1 Reconstitution Tiny lumps, a little foam Tiny lumps,a little foam Tiny lumps, a little foam Tiny lumps, a little foam %Released SD % Released SD % Released SD % Released SD 2 Dissolution 93.61.6 92.9 1.1 90.0 1.1 95.5 1.3 (n = 6) 94.8 1.7 93.3 0.8 90.6 1.6 94.91.2 94.6 2.3 93.4 0.7 90.1 1.5 96.4 1.5 96.2 2.6 93.3 1.1 90.5 1.9 94.41.1 97.7 2.3 92.9 1.1 90.0 1.5 96.1 1.4

It was observed that all samples showed above 90% dissolution in 5minutes, indicating that a blending range of 10-25 minutes and alubrication range of 3-10 minutes have no significant effect on sampledissolution. Blending time and lubrication time is now fixed as 15minutes and 5 minutes respectively as previous trials.

Example 31: Evaluation of Effect of High/Low Lubrication

To evaluate the effect of lubrication on +/−50% deviation of magnesiumstearate level was used to test the effect of lubricant level onformulation physicochemical properties and dissolution. Compositions aregiven in Table 33.

TABLE 33 Composition of DS-89 and 90 Quantity per unit (mg) Goal:High/low lubricant DOE study (500 g scale). Ref. DS-75 (Batch #FSIG-20140826-1) Batch: FSIG-20150325-1 Batch: FSIG-20150325-2 (DS-89)(DS-90) 0.25% magnesium 0.75% magnesium S. # Ingredients stearatestearate 1 Tecovirimat Granulate 346.49 346.49 2 Lactose monohydrate, NF67.26 64.76 (SuperTab 11SD) 3 Methylcellulose, 400 cps, USP 50.00 50.004 Sucralose, NF 10.00 10.00 5 Strawberry flavor, #133.16296 5.00 5.00 6Simethicone Granular Solid (MED- 20.00 20.00 342), ESP 7 Magnesiumstearate, NF 1.25 3.75 Total weight (mg) 500.00 500.00

The batch sire of each composition was 0.500 kg. In general, theformulation procedure involved the following steps:

-   -   1. Passing of the Tecovirimat granules and granular Simethicone        through Quadro Comil equipped with 2B3039R03125173*(991) screen.    -   2. Passing of the Tecovirimat granulate and granular Simethicone        through a #20 screen.    -   3. Passing of lactose through a #20 screen, then addition of        Flavor on lactose with geometric mixing using spatula.    -   4. Passing of polymer and sucralose through a #40 screen.    -   5. Blending of the Tecovirimat-Simethicone blend and other        extragranular components in the V-blender for 15 minutes.    -   6. Passing of magnesium stearate through a #40 screen, then        addition as a lubricant to above milled blend and lubricate for        5 minutes.    -   7. Evaluation of the physicochemical properties of blend (Table        34).    -   8. Transfer of 10 doses of blend to a 100 cc glass bottle. Add        water Q.S. to 50 mL. Shake well to mix the content. Evaluate the        physicochemical properties of suspension (Table 35).    -   9. Packing of 20 doses of blend in Stick pack PAKVF2.5M Fin seal        pouches (part #25M0275FS06); size 2.5 inch×6 inch. Heat-seal        properly. Prepare 3 pouches for dissolution study (Table 36).

TABLE 34 Characterization of blend DS-89 and DS-90 Batch:FSIG-20150325-1 Batch: FSIG- S# Property (DS-89) 20150325-2 (DS-90) 1Appearance White powder White powder 2 Flow of Lubricated Blend (Flodex24 24 Orifice mm) 3 Bulk Density (g/cc) 0.544 0.531 Tap Density (g/cc)0.706 0.698 Compressibility Index (%) 22.9 23.9 4 Granules Retained onSieve # 20 0.01 0.06 (opening size 0.850 mm) (%) Granules Retained onSieve # 30 4.32 4.30 (opening size 0.600 mm) (%) Granules Retained onSieve # 40 10.01 9.89 (opening size 0.425 mm) (%) Granules Retained onSieve # 50 10.89 13.49 (opening size 0.300 mm) (%) Granules Retained onSieve # 60 6.16 5.92 (opening size 0.250 mm) (%) Granules Retained onSieve # 80 15.86 16.26 (opening size 0.180 mm) (%) Retained on Pan (size<0.180 mm) 52.74 50.08 (%) Mean Size (mm) 0.145 0.153

TABLE 35 Characterization of suspension of DS-89 and DS-90 Batch:FSIG-20150325-1 Batch: FSIG-20150325-2 S# Property (DS-89) (DS-90) 1Reconstitution After manual shaking, no fish eye is After manualshaking, 2 fish eyes are observed, disperse very well. observed atbottom of bottle. 2 Appearance after White dispersion White dispersionreconstitution 3 pH of suspension 6.07 6.12 4 Microscopic Particle size3.22 ± 2.91 μm. No Particle size 3.26 ± 3.00 μm. No observationagglomeration observed. agglomeration observed. 5 Physical stability Nophase separation or agglomeration. No phase separation or agglomeration.6 Forced settling Redispersible Redispersible and redispersibility 7Observation of 10 min 30 min 24 hr 10 min 30 min 24 hr sedimentation At25° C. Sedimentation 1.00 1.00 1.00 1.00 1.00 1.00 coefficientSeparation None None Second layer None None Second layer (22% height)(23% height) Redispersibility Redispersible Redispersible RedispersibleRedispersible Redispersible Redispersible At 5° C. Sedimentation 1.001.00 1.00 1.00 1.00 1.00 coefficient Separation None None Second layerNone None Second layer (20% height) (36% height) RedispersibilityRedispersible Redispersible Redispersible Redispersible RedispersibleRedispersible

TABLE 36 Dissolution of DS-89 and DS-90 (see FIG. 6) Property Batch:FSIG-20150325-1 Batch: FSIG-20150325-2 Time (DS-89) (DS-90) S# (min) %Released SD % Released SD 1 Dissolution 5 91.2 0.7 94.8 2.2 (n = 6) 1092.6 0.5 95.5 1.8 15 92.9 1.1 95.1 1.5 30 92.8 1.1 95.6 2.3 45 93.8 1.895.8 2.0

The quantity of magnesium stearate at 0.25% and 0.75% level of theformulation did not show any difference in physicochemical properties aswell as dissolution of the product.

Example 15: Effect of Milling on Particle Size and Size Distribution ofTecovirimat Granules

The purpose is to study the effect of milling on particle size and sizedistribution of Tecovirimat granules. 100 g of Tecovirimat granules fromSiga were used to test the size distribution. 110 g of Tecovirimatgranules from the same Siga Lot # were passed through Quadra Comilequipped with 2B039R03125173*(991) screen, from which 100 g were weighedfor size distribution test. The results are shown in Table 37.

TABLE 37 Particle size and size distribution of Tecovirimat Granulesbefore/after milling Lot # Lot # 1401165 1401165 (before (after S#Property milling) milling) 1 Granules Retained on Sieve # 20 (opening0.05 0.04 size 0.850 mm) (%) Granules Retained on Sieve # 30 (opening6.38 4.47 size 0.600 mm) (%) Granules Retained on Sieve # 40 (opening10.34 12.31 size 0.425 mm) (%) Granules Retained on Sieve # 50 (opening10.80 11.64 size 0.300 mm) (%) Granules Retained on Sieve # 60 (opening5.05 5.36 size 0.250 mm) (%) Granules Retained on Sieve # 80 (opening8.48 8.55 size 0.180 mm) (%) Granules Retained on Sieve # 100 (opening4.74 4.70 size 0.150 mm) (%) Retained on Pan (size <0.150 mm) (%) 54.1752.93 Mean Size (mm) 0.150 0.150

It was observed that no significant different between the sizedistribution of Tecovirimat granules before or after milling.

Example 16: Evaluation of Pre-Dilution and as is Simethicone BeforeMixing/Blending

Simethicone granular grade is currently prediluted/milled withTecovirimat granules. The pre-dilution and no-dilution/as is Simethiconebefore mixing were compared, to establish the method of dilution thatcan be commercially reproduced at large scale. Compositions are given inTable 38.

TABLE 38 Composition of DS-91 and DS-92 Quantity per unit (mg) Goal:Simethicone pre-dilution or no-dilution (500 g scale). Ref. DS-75 (Batch# FSIG- 20140826-1) Batch: FSIG- Batch: FSIG- 20150407-1 20150407-2(DS-91) (DS-92) pre-diluted undiluted S. # Ingredients SimethiconeSimethicone 1 Tecovirimat Granulate 346.49 346.49 2 Lactose monohydrate,NF 66.01 66.01 (SuperTab 11SD) 3 Methylcellulose, 400 cps, USP 50.0050.00 4 Sucralose, NF 10.00 10.00 5 Strawberry flavor, #133.16296 5.005.00 6 Simethicone Granular Solid (MED- 20.00 20.00 342), USP 7Magnesium stearate, NF 2.50 2.50 Total weight (mg) 500.00 500.00

The batch size of each composition was 0.500 kg. In general, theformulation procedure involved the following steps:

-   -   1. For DS-91, passing of the Tecovirimat granules and granular        Simethicone through Quadro Comil equipped with        2B039R03125173*(991) screen, then passing of the Tecovirimat        granulate and granular Simethicone through a #20 screen;    -   2. For DS-92, passing of the Tecovirimat granulate through        Quadro Comil equipped with 2D039R03125173*(991) screen; then        passing of granular Simethicone through a #20 screen;    -   3. Passing of lactose through a #20 screen, then addition of        Flavor on lactose with geometric mixing using spatula;    -   4. Passing of polymer and sucralose through a #40 screen;    -   5. Blending of Tecovirimat granulate and all the extragranular        components in the V-blender for 15 minutes;    -   6. Passing of magnesium stearate through a #40 screen, then        addition as a lubricant to above milled blend and lubricate for        5 minutes;    -   7. Evaluation of the physicochemical properties of blend (Table        39);    -   8. Transfer of 10 doses of blend to a 100 cc glass bottle. Add        water Q.S. to 50 mL. Shake well to mix the content. Evaluate the        physicochemical properties of suspension (Table 40);    -   9. Packing of 20 doses of blend in Stick pack PAKVF2.5M Fin seal        pouches (part #25M0275FS06); size 2.5 inch×6 inch. Heat-seal        properly. Prepare 3 pouches for dissolution study (Table 41).

TABLE 39 Characterization of blend DS-91 and DS-92 Batch: FSIG- Batch:FSIG- 20150407-1 20150407-2 S# Property (DS-91) (DS-92) 1 AppearanceWhite powder White powder 2 Flow of Lubricated Blend (Flodex 24 26Orifice mm) 3 Bulk Density (g/cc) 0.533 0.525 Tap Density (g/cc) 0.7010.700 Compressibility Index (%) 24.0 25.0 4 Granules Retained on Sieve #20 0.03 0.06 (opening size 0.850 mm) (%) Granules Retained on Sieve # 304.26 4.06 (opening size 0.600 mm) (%) Granules Retained on Sieve # 4010.10 10.49 (opening size 0.425 mm) (%) Granules Retained on Sieve # 5010.87 10.11 (opening size 0.300 mm) (%) Granules Retained on Sieve # 603.50 4.18 (opening size 0.250 mm) (%) Granules Retained on Sieve # 8012.92 13.80 (opening size 0.180 mm) (%) Retained on Pan (size <0.180 mm)58.32 57.30 (%) Mean Size (mm) 0.133 0.135

TABLE 40 Physicochemical Properties of Suspension of DS-91 and DS-92Batch: FSIG-20150407-1 Batch: FSIG-20150407-2 S# Property (DS-91)(DS-92) 1 Reconstitution After manual shaking, no fish eye is Aftermanual shaking, no fish eye is observed, disperse very well. observed,disperse very well. 2 Appearance after White dispersion. Whitedispersion. reconstitution Foaminess similar to DS-92 Foaminess similarto DS-91. 3 pH of suspension 6.11 6.05 4 Microscopic Particle size 3.02± 2.03 μm. No Particle size 3.14 ± 2.47 μm. No observation agglomerationobserved. agglomeration observed. 5 Physical stability No phaseseparation or agglomeration. No phase separation or agglomeration. 6Forced settling Redispersible Redispersible and redispersibility 7Observation of 10 min 30 min 24 hr 10 min 30 min 24 hr sedimentation At25° C. Sedimentation 1.00 1.00 1.00 1.00 1.00 1.00 coefficientSeparation None None Second layer None None Second layer (28% height)(33% height) Redispersibility Redispersible Redispersible RedispersibleRedispersible Redispersible Redispersible At 5° C. Sedimentation 1.001.00 1.00 1.00 1.00 1.00 coefficient Separation None None Second layerNone None Second layer (28% height) (33% height) RedispersibilityRedispersible Redispersible Redispersible Redispersible RedispersibleRedispersible

TABLE 41 Dissolution of DS-91 and DS-92 Property Batch: FSIG-20150407-1Batch: FSIG-20150407-2 Time (DS-91) (DS-92) S# (min) % Released SD %Released SD 1 Dissolution 5 94.7 2.3 92.2 1.2 (n = 6) 10 94.6 1.9 91.31.2 15 94.2 1.2 91.6 1.3 30 93.8 1.1 90.6 1.2 45 94.9 2.4 91.0 4.0

It was observed that before blending when passing through the #20screen. Simethicone with no-dilution partly stuck on sieve (FIGS. 8 Aand B), while the pre-diluted and co-milled Simethicone and Tecovirimatgranules passed through #20 screen easily (FIGS. 8 C and D). After sieveshaking fir size distribution analysis, big clumps from DS-92 remainedon #20 screen (FIG. 9 ), indicating the formation of big Simethiconelumps when no-dilution before mixing.

FIG. 8 shows an observation when passing simethicone or co-milledsimethicone-Tecovirimat granules through #20 screen. A and B:no-dilution simethicone stuck on screen. C and D: pre-diluted andco-milled simethicone-Tecovirimat granules passed screen easily withoutsticking.

FIG. 9 shows retained clumps on #20 screen after sieve shaking of 100 gDS-92.

Example 17: Evaluation of Simethicone from Alternate Source

Currently Simethicone Granular Solid (MED-342) from Nusil Technologieswas used. An alternate source of Simethicone-Simethicone 50% Powder fromAIC was used to test the effect on formulation. The pre-dilution andno-dilution of simethicone before mixing were compared. Compositions armgiven in Table 41.

TABLE 41 Composition of DS-93 and DS-94 Quantity per unit (mg) Goal:Simethicone alternate source (500 g scale). Ref. DS-75 (Batch #FSIG-20140826-1) Batch: FSIG- Batch: FSIG- 20150421-1 20150421-2 (DS-93)(DS-94) pre-diluted Undiluted S. # Ingredients simethicone simethicone 1Tecovirimat Granulate 346.49 346.49 2 Lactose monohydrate, 74.01 74.01NF (SuperTab 11SD) 3 Methylcellulose, 400 50.00 50.00 cps, USP 4Sucralose, NF 10.00 10.00 5 Strawberry flavor, 5.00 5.00 #133.16296 6Simethicone 50% 12.00 12.00 Powder 7 Magnesium stearate, 2.50 2.50 NFTotal weight (mg) 500.00 500.00

The batch size of each composition was 0.500 Kg. Detailed experimentalprocedures and results of each trial formulation were recorded in theexecuted batch records. In general, the formulation procedure involvedthe following steps:

-   -   1. For DS-93, passing of the Tecovirimat granules and        Simethicone powder through Quadro Comil equipped with        2D039R03125173*(991) screen, then passing of the Tecovirimat        granulate and Simethicone powder through a #20 screen;    -   2. For DS-94, passing of the Tecovirimat granulate through        Quadro Comil equipped with 2B039R03125173*(991) screen; then        passing of Simethicone powder through a #20 screen;    -   3. Passing of lactose through a #20 screen, then addition of        Flavor on lactose with geometric mixing using spatula;    -   4. Passing of polymer and sucralose through a #40 screen;    -   5. Blending of Tecovirimat granulate and all the extragranular        components in the V-blender for 15 minutes;    -   6. Passing of magnesium stearate through a #40 screen, then        addition as a lubricant to above milled blend and lubricate for        5 minutes;    -   7. Evaluation of the physicochemical properties of blend (Table        43);    -   8. Transfer of 10 doses of blend to a 100 cc glass bottle. Add        water Q.S. to 50 mL. Shake well to mix the content. Evaluate the        physicochemical properties of suspension (Table 44);    -   9. Packing of 20 doses of blend in Stick pack PAKVF2.5M Finseal        pouches (part #25M0275FS06); size 2.5 inch×6 inch. Heat-seal        properly. Prepare 3 pouches for dissolution study (Table 45).

TABLE 43 Characterization of blend DS-93 and DS-94 Batch: FSIG- Batch:FSIG- 20150421-1 20150421-2 S# Property (DS-93) (DS-94) 1 AppearanceWhite powder White powder 2 Flow of Lubricated Blend (Flodex 20 20Orifice mm) 3 Bulk Density (g/cc) 0.547 0.540 Tap Density (g/cc) 0.7200.720 Compressibility Index (%) 24.0 25.0 4 Granules Retained on Sieve #20 0.02 0.02 (opening size 0.850 mm) (%) Granules Retained on Sieve # 303.23 2.81 (opening size 0.600 mm) (%) Granules Retained on Sieve # 408.73 8.52 (opening size 0.425 mm) (%) Granules Retained on Sieve # 509.28 8.48 (opening size 0.300 mm) (%) Granules Retained on Sieve # 603.56 3.75 (opening size 0.250 min) (%) Granules Retained on Sieve # 8013.96 11.28 (opening size 0.180 mm) ( %) Retained on Pan (size <0.180mm) 61.23 65.15 (%) Mean Size (mm) 0.118 0.108

TABLE 44 Physicochemical properties of suspension of DS-93 and DS-94Batch: FSIG-20150421-1 Batch: FSIG-20150421-2 S# Property (DS-93)(DS-94) 1 Reconstitution After manual shaking, no fish eye is Aftermanual shaking, no fish eye is observed, disperse very well. observed,disperse very well. 2 Appearance after White dispersion, foaminesssimilar to White dispersion, foaminess similar to reconstitution DS-94,more foam than DS-91 and DS-92. DS-93, more foam than DS-91 and DS-92. 3pH of suspension 6.11 6.07 4 Microscopic Particle size 3.40 ± 3.04 μm.No Particle size 3.46 ± 2.96 μm. No observation agglomeration observed.agglomeration observed. 5 Physical stability No phase separation oragglomeration. No phase separation or agglomeration. 6 Forced settlingand Redispersible Redispersible redispersibility 7 Observation of 10 min30 min 24 hr 10 min 30 min 24 hr sedimentation At 25° C. Sedimentation1.00 1.00 1.00 1.00 1.00 1.00 coefficient Separation None None Secondlayer None None Second layer (26% height) (29% height) RedispersibilityRedispersible Redispersible Redispersible Redispersible RedispersibleRedispersible At 5° C. Sedimentation 1.00 1.00 1.00 1.00 1.00 1.00coefficient Separation None None Second layer None None Second layer(25% height) (25% height) Redispersibility Redispersible RedispersibleRedispersible Redispersible Redispersible Redispersible

TABLE 45 Dissolution of DS-93 and DS-94 Property Batch: FSIG-20150421-1Batch: FSIG-20150421-2 Time (DS-93) (DS-94) S# (min) % Released SD %Released % Released 1 Dissolution 5 82.5 1.7 89.3 89.3 (n = 6) 10 84.71.4 86.8 86.8 15 85.4 0.7 86.9 86.9 30 86.5 1.1 88.2 88.2 45 86.2 1.988.4 88.4

It was observed that the undiluted simethicone 50% powder passed #20screen easily without any sticking. The flowability of DS-93 and DS-94using simethicone powder was better than that of previous batches usinggranular simethicone. The suspensions of DS-93 and DS-94 afterreconstitution were similarly loamy, both containing much more foam thanDS-91 and DS-92. Therefore the antifoaming effect of simethicone powderis not as efficient as that of granular simethicone.

Example 18: Taste Assessment of the Aqueous Pharmaceutical SuspensionFormulations

The taste of the aqueous pharmaceutical suspension formulationsaccording to the present invention is critically important to thesuccessful oral administration.

Consequently the present invention provides a palatable powder forsuspension dosage form of Tecovirimat which is suitable for pediatricand geriatric dosing

The following examples identify and quantify the sensory attributes(basic tastes, e.g., bitterness; aromatics and trigeminal effects) of aseries of Tecovirimat aqueous suspensions.

Six experienced pharmaceutical sensory panelists were used to evaluatethe above mentioned sensory attributes.

Samples were evaluated using the Flavor Profile method I of descriptivesensory analysis to identify, characterize and quantify the sensoryattributes of the study samples. The Flavor Profile method wasoriginally developed to assist The Upjohn Company in identifying offtastes in their gelatin capsules and provides a complete description ofthe sensory attributes of products. e.g., texture, aroma, taste,mouthfeel.

The method consists of formal procedures for describing and assessingthe aroma (if appropriate) and flavor of a product in a reproduciblemanner. The Flavor Profile terms are shown in FIG. 11 .

Flavor Profile is used to identify the individual attributes of productflavor, including:

-   -   1. Basic tastes: sweet, sour, salty, and bitter;    -   2. Aromatics: volatile components perceived by the olfactory        system via the nasopharyngeal passage (retronasal) and    -   3. Feeling factors: numbing, cooling, warming, burning, drying,        oily, astringent, etc.

Flavor Profile also includes measures of the strength, or intensity, atwhich these character notes appear; the order in which the characternotes appear; and a description of all sensations i.e. basic tastes,feeling factors, and aromatics remaining at specified time intervalsafter swallowing.

For some oral pharmaceuticals texture attributes such as hardness(chewable tablets) or particulates/grittiness (chewable tablets,sachets, suspensions) are also noted and assessed.

For oral pharmaceuticals, both the initial flavor quality and theaftertaste flavor quality are important to patient acceptability, andtherefore it is important that each be evaluated. The initial flavorcharacteristics of the study products were evaluated during the first10-20 seconds, and the aftertaste attributes were evaluated at multipletime intervals to 30 minutes as described below.

Sample Constitution and Taste Evaluation Protocols

The compounded Tecovirimat powder for suspension, micronized TecovirimatAPI as well as tecovirimat granules taste assessment samples wereconstituted immediately prior to evaluations as follows:

-   -   1. The API-containing powder in an amber bottle was agitated to        ensure the powder moves around freely.    -   2. The purified (reverse osmosis) water premeasured was added to        each bottle containing the powder.    -   3. The bottles were mixed by hand for a few minutes. The        unflavored bottles were mixed vigorously and the flavored        bottles were mixed gently.    -   4. 5 mL samples were taken from each test formulation and        dispensed to each panelist for evaluation.

The panelists evaluated the constituted samples as follows:

-   -   1. The panelists cleansed their palates with spring water and        unsalted crackers.    -   2. 5 mL of sample was dispensed into individual 1-ounce plastic        cups using a graduated oral syringe and distributed to each        panelist.    -   3. Starting at the same time, the panelists poured the sample        directly in to their mouths, swished the contents around the        oral cavity for 10 seconds and expectorated. During this time        the panelists independently evaluated and recorded the initial        flavor characteristics.    -   4. The panelists then independently evaluated and recorded the        aftertaste characteristics at periodic intervals out to 30        minutes as flavor persisted.    -   5. The panelists recited their individual results and a        preliminary Flavor Profile was generated for the sample.    -   6. Steps 1 through 4 were repeated for a second evaluation of        the sample using the preliminary Flavor Profile from Step 5 as a        guide, with the panelists noting any necessary modifications.    -   7. The panelists recited their individual results and a final        Flavor Profile was developed for the sample.        Flavor Leadership Criteria

The flavor quality of the flavored drug product prototypes wasinterpreted using the relevant Flavor Leadership Criteria. Researchreveals that the perennial sales leaders in many categories, includingpharmaceuticals, have a set of sensory characteristics in common, whichare known as the Flavor Leadership Criteria. The flavor profilesassociated with products typically having the highest sales within aproduct category possess the following characteristics:

-   -   1. Have a quickly recognizable identifying flavor;    -   2. Develop full flavor that rapidly blends with and covers the        active and base characteristics;    -   3. Have no unpleasant mouth sensations (e.g., tongue sting);    -   4. Have no off-notes in the early impression or in the        aftertaste;    -   5. Have a short (or appropriate) aftertaste.

The concepts of Flavor Leadership were used to interpret the sensoryanalysis results and are described more fully below.

Immediate Impact of the Identifying Flavor.

Flavor Leaders exhibit an immediate impact of the identifying flavor.When a consumer tastes a product, the first character notes provide forproduct identification and set expectations for the remainder of theflavor experience. For example, many inexpensive chocolates have aninitial waxy impression whereas high-quality chocolates are identifiedby an initial chocolate flavor and cocoa butter mouthfeel. Unfortunatelyfor many oral pharmaceuticals, the first impression is bitterness or anaromatic off-note (e.g., green stemmy, musty, chalky) that many patientsfind unacceptable.

Rapid Development of Balanced, Full Flavor.

A well-blended flavor is key to product success. Flavor Leaders have aflavor that develops rapidly and is full bodied and well balanced.Blended flavor means that a complex body of underlying sensoryimpressions that are not separately identified support the expectedcharacter notes. For example, Coca-Cola® comprises hundreds ofindividual flavoring components that are hard to single outindividually, the components are very well blended. Unlike most foodsand beverages, the challenge for pharmaceuticals is to “blend away” thenegative sensory attributes of the drug substance, while simultaneouslyminimizing the number of excipients in the formulation. Amplitude is anintegrative measure of balance and fullness (see FIG. 11 ). It is anoverall measure of the quality of the initial flavor and has been shownto correlate with palatability and patient acceptance. Amplitude of 1 isappropriate for most oral pharmaceuticals.

Compatible Mouthfeel Factors.

Flavor leader have a mouthfeel that is compatible with consumers'expectations. Many drug actives and excipients can cause trigeminaleffects such as tongue sting or throat burn that may be unacceptable topatients and consumers. For example, a slight amount of mouth irritationwould be acceptable in a citrus flavored formulation (“citrus rind mouthirritation”) but would be totally out-of-context in a bubblegum flavoredformulation. Unexpected or stronger than expected mouthfeel factors canhave an adverse effect on patient acceptability.

Examples of excipients that produce trigeminal effects include:

-   -   1. Methyl and propyl paraben (common preservatives in many oral        pharmaceuticals) produce a tongue sting and numbing that can be        unacceptable above a certain level.    -   2. Benzyl alcohol (solvent/preservative) produces both tongue        sting and bum.        No “Off-Flavors.”

Flavor leaders are notable for their consistent lack of off-flavors. Anoff-flavor is the appearance of an unexpected or unacceptable characternote (off-note). For most oral pharmaceuticals the API is the principalsource of off-notes, which can include basic tastes (e.g., bitter)and/or aromatics (e.g., sulfurous). Other sources of off-notes includeexcipients. e.g., paraben aromatics poor flavor systems that result interpy, solventy, or perfumy off-notes, packaging interactions that“taint” or transfer of off-notes from the package to the product and“flavor scalping” or transfer (loss) of flavor aromatics from theproduct to the package.

Short (or Appropriate) Aftertaste.

The last impression i.e. the aftertaste is especially important toflavor quality. Aftertaste is caused by the persistence of one or a fewcharacter notes well after swallowing. For most products, a short, cleanaftertaste is important. Products with a short, clean aftertasteencourage the consumer to take another bite or sip, and thereby toconsume more of the product. For example, one of the major complaintsabout saccharin is its particularly long, bitter aftertaste and throatcatch.

However, the goal for pharmaceuticals is patient compliance, notconsumption. For many APIs, the aftertaste is most critical as manyflavor systems provide adequate coverage in the early aftertaste but thebeneficial effects quickly decrease, exposing the API.

As a general rule it is easier to mask a strongly bitter (or other)tasting API that “fades” quickly (steep decay curve) versus a moderatelybitter API initially that lingers well into the aftertaste (flat decaycurve). In any event, the challenge for the formulator is to mask thetaste of the active throughout the duration of the aftertaste—be it 30seconds or 30 minutes.

Drug Product

The study samples in Table 46 were compounded by Custom MedicinePharmacenter, a compounding-only pharmacy in Beverly, Mass. followingSIGA-approved batch records (logged formula worksheets). The Tecovirimatdrug active was supplied by SIGA as bulk powder (granulated andmicronized), and the excipients provided by SIGA approved suppliers.

TABLE 46 Study Formulations at 40 mg/mL Tecovirimat Concentration Form#3 Form #4 Form # 1 Form #2 (API (API (Strawberry (Cherry Granulated 200Micronized 200 mg/ml) mg/ml) mg/ml) mg/ml) Batch Weight Batch WeightBatch Weight Batch Weight Ingredient Manufacturer Lot Number Expiry (g)(g) (g) (g) Tecovirimat, Granulate SIGA 1401165 Sep. 14, 2015 3.4653.465 3.465 — Tracovirimat SIGA 9199001 Aug. 25, 2016 — — — 2.090Monohydrate, Micronized Sucralose EMD K93441194 Mar. 8, 2016 0.100 0.100— — Simethicone Granular NUSIL 66777 May 12, 2015 0.200 0.200 — — SolidMethocel, A4C DOW 2H22012N11 Aug. 22, 2015 0.500 0.500 — StrawberryFlavor, Bell Flavors 521145 Jun. 23, 2016 0.500 — — — 133.1529 CherryFlavor, 23950 Virginia Dare T02198 Aug. 23, 2016 — 0.030 — — LactoseMonohyrdrate DFE Pharma 10700181 Feb. 28, 2015 0.685 0.705 — — PurifiedWater CMP — Dec. 31, 2015 47 mL 47 mL 47 mL 50 mL Volume Tasted 50 mL 50mL 50 mL 50 mLTaste Assessment Days

The four formulations shown in Table 46 were evaluated over a three-dayperiod as necessary to ensure that the maximum daily exposure of 600 mgper day was not exceeded. The schedule was as follows:

Day 1:

Tecovirimat Formulation 3 (200 mg/5 mL)—Tasted twice

Tecovirimat Formulation 4 (200 mg/5 mL)—Tasted once

Day 2:

Tecovirimat Formulation 4 (200 mg/5 mL)—Tasted once

Tecovirimat Formulation 1 (200 mg/5 mL)—Tasted twice

Day 3:

Tecovirimat Formulation 1 (200 mg/5 mL)—Tasted once

Tecovirimat Formulation 2 (200 mg/5 mL)—Tasted twice

Flavor Profile Results

The panelists evaluated the samples by the procedure outlined above. Theresults are summarized by formulation in tabular and graphical formatsbelow. The tabular format contains the final Flavor Profile for thesample along with interpretation of the results using the FlavorLeadership Criteria.

The challenge for many oral pharmaceuticals is to mask the critical(“undesirable”) sensory characteristics of the active in the initialflavor and throughout the aftertaste.

To visualize the temporal sensory effects (aftertaste) it is useful toplot selected attribute intensities as a function of time. Thus,following each tabular summary is a graph. In each graph, the area abovea slight intensity (>1) has been shaded. Negative sensorycharacteristics above this intensity are clearly perceptible to patientsand are often found to be unacceptable.

To increase the likelihood of product acceptability the intensity ofnegative sensory characteristics should remain below this criticalintensity throughout a product's flavor profile.

Tecovirimat—Formulation 3 (Granules)

Tecovirimat (200 mg/mL) Formulation #3 (Granule) is characterized bymusty aromatic off notes, bitter basic taste and tannin/chalky mouthfeels as shown in Table 47.

TABLE 47 Flavor Profile for Tecovirimat - Formulation 3 (Granules)Flavor Profile SIGA Tecovirimat Formulation #3 200 mg/mL (Granule)Initial 1 Min 3 Min 5 Min 10 Min 15 Min 20 Min 25 Min 30 Min MustyAromatic 2 1½ 1 ½ — — — — — Sour ½ — — — — — — — — Bitter 1 1-1½ 1 ½ ½ ½0 — — Chalky Mouthfeel 1 1 ½-1 ½ — — — — — Tannin Mouthfeel 1½ 1-1½ 1 1— — — — — Drying Mouthfeel ½ 1 1½ 1½ 1-1½ 1-1½ 1 ½ — Flavor LeadershipInterpretation 1 - Aromatic Identity 2- Amplitude 3- Mouthfeel 4-Off-Notes 5-Aftertaste Not applicable Not applicable Chalky, tannin andSlight-to-moderate Lingering for unflavored for unflavored dryingmouthfeels intensity bitterness bitterness, products products andmoderate mouthfeels and intensity musty aromatic off-notes aromaticoff-notes

The musty aromatic off-notes, bitterness and tannin mouthfeel of theTecovirimat granules (Formulation #3) lingered at patient-perceptiblelevels (≥1) for about 3 minutes in the Aftertaste, see FIG. 12 .

Tecovirimat—Formulation 4 (Micronized)

Tecovirimat (200 mg/mL) Formulation #4 (micronized API) is characterizedby aromatic offnotes (chalky, soapy/waxy), bitter basic taste andtannin/chalky mouthfeels, though generally lower in intensity than theAPI granules as shown in Table 48.

TABLE 48 Flavor Profile for Tecovirimat - Formulation 4 (Micronized)Flavor Profile SIGA Tecovirimat Formulation #4 200 mg/mL (MicronizedAPI) Initial 1 Min 3 Min 5 Min 10 Min 15 Min 20 Min 25 Min 30 Min ChalkyAromatic 1-1½ 1 ½ — — — — — — Soapy/Waxy 1-1½ 1 ½ — — — — — — AromaticBitter 1 1-1½ ½-1 ½ ½ 0-½ — — Chalky Mouthfeel ½-1 1 1-1½ — — — — — —Tannin Mouthfeel 1 1 1 ½-1 ½ — — — — Drying Mouthfeel ½ 1 1 1 1 1 ½ 0-½— Flavor Leadership Interpretation 1 - Aromatic Identity 2- Amplitude 3-Mouthfeel 4- Off-Notes 5-Aftertaste Not applicable for Not applicableChalky, tannin and Slight-to-moderate Lingering unflavored products forunflavored drying mouthfeels intensity bitterness bitterness, productsand moderate mouthfeels and intensity musty aromatic off-notes aromaticoff-notes

The negative (aversive) sensory attributes of the micronized API(Formulation #4) are marginally above a slight (1) intensity, which isthe perception threshold for most patients as shown in FIG. 13 .

Tecovirimat—Formulation 1 (Strawberry)

Tecovirimat Formulation #1 (Strawberry) is somewhat low in initialflavor quality as measured by Amplitude (balance and fullness) as shownin Table 49.

TABLE 49 Flavor Profile for Tecovirimat - Formulation 1 (Strawberry)Flavor Profile SIGA Tecovirimat Formulation #1 200 mg/mL (Strawberry)Initial 1 Min 3 Min 5 Min 10 Min 15 Min 20 Min 25 Min 30 Min Amplitude 1Sweet 1½ 1-1½ ½-1 ½ 0-½ — — — — Sour ½ — — — — — — — — Strawberry 1½ 1 ½— — — — — — Aromatics(Fresh and Cream) Chalky/Musty 1½ 1 ½ 0-½ — — — — —Aromatic Bitter 1 ½-1 ½ ½ 0-½ — — — — Chalky Mouthfeel 1 1 1 ½ — — — — —Tannin Mouthfeel ½-1 1 ½-1 ½ ½ 0-½ — — — Drying Mouthfeel — 1 1½ 1 1 1 1½ — Synthetic — ½-1 ½ 0-½ — — 1 — — Sweetener Sensation (SSS) FlavorLeadership Interpretation 1 - Aromatic Identity 2- Amplitude 3-Mouthfeel 4- Off-Notes 5-Aftertaste Slight-to-moderate A low level ofChalky, tannin, Slight intensity Lingering basic intensity strawberrybalance and drying and SSS bitterness and tastes, aromatic off-flavoring aromatics fullness mouthfeels slight-to-moderate notes andintensity mouthfeels chalky/musty aromatic off-notes

The flavor system (flavoring aromatics and sweet basic taste) ofFormulation #1 (Strawberry) provides reasonable coverage of the bitterbasic taste and chalky/musty aromatics as shown in FIG. 14 .

Tecovirimat—Formulation 2 (Cherry)

As shown in Table 50, Tecovirimat Formulation #2 (Cherry) is slightlylower in initial flavor quality than the Formulation #1 (Strawberry) asmeasured by Amplitude.

TABLE 50 Tecovirimat - Formulation 2 (Cherry) Flavor Profile SIGATecovirimat Formulation #2 200 mg/mL (Cherry) Initial 1 Min 3 Min 5 Min10 Min 15 Min 20 Min 25 Min 30 Min Amplitude ½-1 Sweet 1½ 1-1½ ½-1 ½ 0-½0-½ Sour ½ 0-½ — — — — — — — Strawberry 1½ 1 ½ — — — — — —Aromatics(Fresh and Cream) Chalky/Musty 1½ 1 ½ — — — — — — AromaticBitter 1 1 ½-1 ½ ½ — — — — Chalky Mouthfeel 1 1-½ 1 ½ — — — — — TanninMouthfeel 1 1-½ 1 ½ ½ 0-½ — — — Drying Mouthfeel — 1 1-1½ 1-1½ 1 1 1 ½ —Synthetic — 1 ½-1 ½ ½ — — — — Sweetener Sensation (SSS) FlavorLeadership Interpretation 1 - Aromatic Identity 2- Amplitude 3-Mouthfeel 4- Off-Notes 5-Aftertaste Slight-to-moderate A low level ofChalky, tannin, Slight intensity Lingering basic intensity strawberrybalance and drying and SSS bitterness and tastes, aromatic off-flavoring aromatics fullness mouthfeels slight-to-moderate notes andintensity mouthfeels chalky/musty aromatic off-notes

The flavor system (flavoring aromatics and sweet basic taste) ofFormulation #2 (Cherry) provides reasonable coverage of the bitter basictaste and chalky/musty aromatics as shown in FIG. 14 .

The results show that he unsweetened/unflavored Tecovirimat formulationsare characterized by aromatic offnotes, (musty, chalky, soapy/waxy),bitter basic taste and tannin/chalky mouthfeels. However, overall, thoseattributes arc lower in intensity in the micronized API compared to thegranules.

The negative attributes of the micronized API are near the perceptionthreshold for most patients (i.e., may not be patient-perceptible).

The two sweetened/flavored Tecovirimat suspensions are somewhat low inoverall flavor quality and both flavored suspensions are somewhat low ininitial flavor quality as measured by Amplitude (Target=1.) due to theiraromatic off-notes (chalky/musty), bitter basic taste and mouthfeels(tannin/chalky).

Both flavored suspensions arc somewhat low in flavor and sweetnessimpact (intensity). However the strawberry-flavored suspension isslightly more blended and full (i.e., higher in Amplitude) thancherry-flavored suspension, which was somewhat “solventy”(benzaldehyde-like) in character and both flavored suspensions provide areasonable coverage of the bitter basic taste and chalky/mustyaromatics, though the flavoring aromatics fade quickly.

Thus it can be seen that Tecovirimat is relatively “bland” in flavor(basic tastes, aromatics, mouthfeel and texture), with the micronizedAPI having a lower flavor than the API granules and thesweetened/flavored formulations are somewhat low in flavor quality(strawberry higher than cherry), primarily due to low impact (intensity)and duration of the flavoring aromatics and to a lesser extent theunderlying sweet basic taste.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made, and equivalents may besubstituted, without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope oftile invention.

REFERENCES

-   1. Fenner et al., The epidemiology of smallpox. In: Smallpox and its    eradication. Switzerland; World Health Organization; 1988)-   2. Bray et al., Antiviral Research 58: 101-114 (2003).-   3. Quenelle et al. 2007. Efficacy of delayed treatment with ST-246    given orally against systemic orthopoxvirus infections in mice.    Antimicrobial Agents and Chemotherapy February; 51(2):689-95-   4. Smee et al. (2002) Antimicrob. Agents Chemother. 46:1329-1335)-   5. Vora et al., 2008, Severe eczema vaccinatum in a household    contact of a smallpox vaccine. Clinical Infectious Disease 15;    46(10):1555-61).

The invention claimed is:
 1. A dry suspension comprising4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2-(1H)-yl)-benzamide(Tecovirimat (ST-246)) and simethicone.
 2. A dry suspension according toclaim 1 further comprising at least one suspending agent.
 3. A drysuspension according to claim 2 wherein the suspending agent ismethylcellulose.
 4. A dry suspension according to claim 2 wherein thesuspending agent is hydroxypropyl cellulose.
 5. A dry suspensionaccording to claim 1 further comprising a lubricant.
 6. A dry suspensionaccording to claim 5 wherein the lubricant is magnesium stearate.
 7. Adry suspension according to claim 1 further comprising an excipient. 8.A dry suspension according to claim 7 wherein the excipient is lactosemonohydrate.
 9. A dry suspension according to claim 1 wherein the ST-246is selected from a group consisting of ST-246 polymorph Form I, ST-246polymorph Form II, ST-246 polymorph Form III, ST-246 polymorph Form IV,ST-246 polymorph Form V and ST-246 polymorph Form VI.
 10. A drysuspension according to claim 1 wherein the ST-246 is micronized.
 11. Adry suspension according to claim 1 wherein the ST-246 is granulated.12. A dry suspension according to claim 1 wherein the simethicone isgranular form.
 13. A dry suspension according to claim 1 wherein thesimethicone is in liquid form and adsorbed on lactose monohydrate.
 14. Adry suspension according to claim 1 comprising 0.2 to 6.0 wt %simethicone.
 15. A dry suspension according to claim 3 comprising 1 to 5wt % methylcellulose.
 16. A dry suspension according to claim 4comprising 1.0 to 30 wt % hydroxypropylcellulose.
 17. A dry suspensionaccording to claim 1 wherein the particle size of ST-246 is 0.5 to 10μm.
 18. An aqueous pharmaceutical suspension formulation comprising adry suspension according to claim 1 and water.
 19. A formulationaccording to claim 18 further comprising a pharmaceutically acceptableingredient.
 20. A formulation according to claim 19 wherein thepharmaceutically acceptable ingredient is selected from the groupconsisting of carrier, excipient, diluent, additive, filler, lubricantand binder.
 21. A method of treating orthopoxvirus infections and/oreczema vaccinatum comprising oral administration to a subject in needthereof a formulation according to claim
 18. 22. The method of claim 21,wherein the subject is administered 400 mg to 2000 mg daily of ST-246.23. A process of making the dry suspension according to claim 1,comprising mixing ST-246 with simethicone and optionally at least onesuspending agent, at least one lubricant, at least one excipient, atleast one further anti-foaming agent, at least one sweetener and/or atleast one flavoring.